Neurobiology of Aging - Articles in Press

Transferrin and HFE genes interact in Alzheimer's disease risk: the Epistasis Project - Corrected Proof

2010-09-03

Abstract: Iron overload may contribute to the risk of Alzheimer's disease (AD). In the Epistasis Project, with 1757 cases of AD and 6295 controls, we studied 4 variants in 2 genes of iron metabolism: hemochromatosis (HFE) C282Y and H63D, and transferrin (TF) C2 and -2G/A. We replicated the reported interaction between HFE 282Y and TF C2 in the risk of AD: synergy factor, 1.75 (95% confidence interval, 1.1–2.8, p = 0.02) in Northern Europeans. The synergy factor was 3.1 (1.4–6.9; 0.007) in subjects with the APOEε4 allele. We found another interaction, between HFE 63HH and TF –2AA, markedly modified by age. Both interactions were found mainly or only in Northern Europeans. The interaction between HFE 282Y and TF C2 has now been replicated twice, in altogether 2313 cases of AD and 7065 controls, and has also been associated with increased iron load. We therefore suggest that iron overload may be a causative factor in the development of AD. Treatment for iron overload might thus be protective in some cases.

Issues to ponder when correlating hippocampal neurogenesis to a hippocampal-dependent memory function - Corrected Proof

Ashok K. Shetty — 2010-09-03

Abstract: Simple correlations between the overall hippocampal neurogenesis and the hippocampal-dependent learning and memory functions are common in the neurogenesis field. There is considerable evidence in the literature to link hippocampal neurogenesis to the hippocampal-dependent memory function. However, simple correlations between neurogenesis and memory function, particularly in studies where neither the cause-effect relationship is established nor the other relevant variables are considered, can lead to erroneous conclusions. As reliable and selective neurogenesis ablation techniques are yet to be developed for rat and higher animal models, it is likely that correlative studies between the overall neurogenesis and the memory function will continue in different conditions in these animal models. Such correlations should be acceptable as long as the other variables are considered adequately. Furthermore, in correlative analyses of the learning and memory function with the newly born granule cells, one needs to consider the age of the newly born granule cells because the newly born granule cells will require at least a few weeks of time after their birth to participate in the learning and memory function in rodent models.

Early temporal short-term memory deficits in double transgenic APP/PS1 mice - Corrected Proof

2010-09-03

Abstract: We tested single APP (Tg2576) transgenic, PS1 (PS1dE9) transgenic, and double APP/PS1 transgenic mice at 3 and 6 months of age on the acquisition of a hippocampal-dependent operant “differential reinforcement of low rate schedule” (DRL) paradigm. In this task mice are required to wait for at least 10 seconds (DRL-10s) between 2 consecutive nose poke responses. Our data showed that while single APP and PS1 transgene expression did not affect DRL learning and performance, mice expressing double APP/PS1 transgenes were impaired in the acquisition of DRL-10s at 6 months, but not at 3 months of age. The same impaired double transgenic mice, however, were perfectly capable of normal acquisition of signaled DRL-10s (SDRL-10s) task, a hippocampal-independent task, wherein mice were required to emit responses when the end of the 10-second delay was signaled by a lighting of the chamber. The age-dependent and early deficits of APP/PS1 mice suggest that the appetitive DRL paradigm is sensitive to the amyloid pathology present in double APP/PS1 mice, and that this mouse line represents a good model with which to study the efficacy of therapeutic strategies against Alzheimer's disease.

Age-related effects on cortical thickness patterns of the Rhesus monkey brain - Corrected Proof

2010-09-01

Abstract: The Rhesus monkey is a useful model for examining age-related as well as other neurological and developmental effects on the brain, because of the extensive neuroanatomical homology to the human brain, the reduced occurrence of neurological diseases such as Alzheimer's disease, and the possibility of obtaining relevant behavioral data and post-mortem tissue for histological analyses. In this study, cortical thickness measurements based on a cortical surface modeling technique were applied for the first time to investigate cortical thickness patterns in the rhesus monkey brain, and were used to evaluate regional age related effects across a wide range of ages. Age related effects were observed in several cortical areas, in particular in the somato-sensory and motor cortices, where a robust negative correlation of cortical thickness with age was observed, similar to that found in humans. In contrast, results for monkeys compared with humans show significant interspecies differences in cortical thickness patterns in the frontal and the inferior temporal regions.

Interaction between aging and neurodegeneration in amyotrophic lateral sclerosis - Corrected Proof

2010-08-26

Abstract: We assessed the spontaneous blood-oxygen-level-dependent signal fluctuations in the resting-state brain networks of amyotrophic lateral sclerosis patients and their relation to physiologically sensitive and disease modified functional magnetic resonance imaging parameters.Resting-state functional magnetic resonance imaging was performed at 3 Tesla on 20 amyotrophic lateral sclerosis patients with minimal frontal cognitive dysfunction and 20 age- and sex-matched healthy volunteers. Resting-state network maps were extracted with independent component analysis and group-level statistical analyses were performed to detect disease and disease-by-age interaction effects. Whole-brain global and regional atrophy measures were obtained from same-session structural scans.The sensori-motor network showed significant disease effects, with signals suppressed in patients bilaterally in the primary motor cortex. The default-mode network showed a significant disease-by-age interaction in the posterior cingulate cortex, where signals correlated with age positively in patients and negatively in controls. Both disease and disease-by-age interaction effects were detected in the right fronto-parietal network. Although global atrophy did not show significant differences, regions of reduced gray matter volume were detected in patients compared with controls adjacent to regions of reduced functional connectivity.Our results confirm that resting-state functional magnetic resonance imaging signals in the sensori-motor network are suppressed in amyotrophic lateral sclerosis. A similar suppression is evident in the right fronto-parietal network, possibly reflecting the patients' frontal dysfunction and right-lateralized patterns of regional atrophy. The interaction between disease and aging in the default-mode network unravels a possible mechanism of compensation between motor and extramotor systems emerging as a supplementary functional push to help motor disturbances.

Normal age-related brain morphometric changes: nonuniformity across cortical thickness, surface area and gray matter volume? - Corrected Proof

2010-08-26

Abstract: Normal aging is accompanied by global as well as regional structural changes. While these age-related changes in gray matter volume have been extensively studied, less has been done using newer morphological indexes, such as cortical thickness and surface area. To this end, we analyzed structural images of 216 healthy volunteers, ranging from 18 to 87 years of age, using a surface-based automated parcellation approach. Linear regressions of age revealed a concomitant global age-related reduction in cortical thickness, surface area and volume. Cortical thickness and volume collectively confirmed the vulnerability of the prefrontal cortex, whereas in other cortical regions, such as in the parietal cortex, thickness was the only measure sensitive to the pronounced age-related atrophy. No cortical regions showed more surface area reduction than the global average. The distinction between these morphological measures may provide valuable information to dissect age-related structural changes of the brain, with each of these indexes probably reflecting specific histological changes occurring during aging.

The association between white matter hyperintensities and executive decline in mild cognitive impairment is network dependent - Corrected Proof

2010-08-26

Abstract: White matter hyperintensities (WMH) in Mild Cognitive Impairment (MCI) have been associated with impaired executive functioning, although contradictory findings have been reported. The aim of this study was to examine whether WMH location influenced the relation between WMH and executive functioning in MCI participants (55–90 years) in the European multicenter memory-clinic-based DESCRIPA study, who underwent MRI scanning at baseline (N = 337). Linear mixed model analysis was performed to test the association between WMH damage in three networks (frontal-parietal, frontal-subcortical and frontal-parietal-subcortical network) and change in executive functioning over a 3-year period. WMH in the frontal-parietal and in the frontal-parietal-subcortical network were associated with decline in executive functioning. However, the frontal-subcortical network was not associated with change in executive functioning.Our results suggest that parietal WMH are a significant contributor to executive decline in MCI and that investigation of WMH in the cerebral networks supporting cognitive functions provide a new way to differentiate stable from cognitive declining MCI individuals.

Genetic variations in the CLU and PICALM genes are associated with cognitive function in the oldest old - Corrected Proof

Jonas Mengel-From, Kaare Christensen, Matt McGue, Lene Christiansen — 2010-08-26

Abstract: Recently, two large, and independent genome wide association studies of late-onset Alzheimer's disease (AD) established association with the same rs11136000 variation in the clusterin (CLU) gene. In addition, one variation, rs3851179, in the phosphatidylinositol binding clathrin assembly protein (PICALM) gene and one variation, rs6656401, in the complement component (3b/4b) receptor 1 (CR) gene were associated with AD. Here, we replicate these associations with cognitive functioning in 1380 individuals from the Danish (1905) birth cohort study of the oldest old (92–93 years at intake) using measures of Mini Mental State Examination (MMSE) and a cognitive composite score. We found a significant association between the highly frequent CLU rs11136000 T allele (38%) and better performance on the cognitive composite score (p = 0.016) explaining 0.5% of the mean variation in cognitive composite score, and for men a significant association between the highly frequent PICALM rs3851179 A allele (38%). Better performance was found (p = 0.024), explaining 1.4% of the mean variation in cognitive composite score in men. These alleles correspond to the minor alleles initially found more frequent in controls than in cases of AD.

Stereological quantification of the cerebellum in patients with Alzheimer's disease - Corrected Proof

Kjeld Andersen, Birgitte Bo Andersen, Bente Pakkenberg — 2010-08-23

Abstract: Nonquantitative studies indicate that the cerebellum is neuropathologically affected in Alzheimer's disease; however, no quantitative studies on the subject have yet been conducted. Ten cerebella from elderly female subjects with severe Alzheimer's disease and 10 age- and gender-matched controls were examined. The cerebellum was divided into 5 regions and the Purkinje and granule cell number and density, cortical volume, molecular and granular layer volume and thickness, white matter volume, surface area, and the Purkinje cell gradient were stereologically estimated. There was no significant difference between the groups in Purkinje or granule cell number or density, and no overall difference in Purkinje cell gradient. However, there was a significant 12.7% reduction in total cerebellar volume in the Alzheimer's group and significant localized differences between the groups regarding other parameters. The relative lack of neuropathological changes in the cerebellum of severely demented Alzheimer's patients suggests that neuronal cell bodies on a global scale apparently still are intact.

Age-related increase of sIAHP in prefrontal pyramidal cells of monkeys: relationship to cognition - Corrected Proof

J.I. Luebke, J.M. Amatrudo — 2010-08-20

Abstract: Reduced excitability, due to an increase in the slow afterhyperpolarization (and its underlying current sIAHP), occurs in CA1 pyramidal cells in aged cognitively-impaired, but not cognitively-unimpaired, rodents. We sought to determine whether similar age-related changes in the sIAHP occur in pyramidal cells in the rhesus monkey dorsolateral prefrontal cortex (dlPFC). Whole-cell patch-clamp recordings were obtained from layer 3 and layer 5 pyramidal cells in dlPFC slices prepared from young (9.6 ± 0.7 years old) and aged (22.3 ± 0.7 years old) behaviorally characterized subjects. The amplitude of the sIAHP was significantly greater in layer 3 (but not layer 5) cells from aged-impaired compared with both aged-unimpaired and young monkeys, which did not differ. Aged layer 3, but not layer 5, cells exhibited significantly increased action potential firing rates, but there was no relationship between sIAHP and firing rate. Thus, in monkey dlPFC layer 3 cells, an increase in sIAHP is associated with age-related cognitive decline; however, this increase is not associated with a reduction in excitability.

White matter hyperintensities alter functional organization of the motor system - Corrected Proof

2010-08-19

Abstract: Severe white matter hyperintensities (WMH) represent cerebral small vessel disease and predict functional decline in the elderly. We used fMRI to test if severe WMH impact on functional brain network organization even before clinical dysfunction. Thirty healthy right-handed/footed subjects (mean age, 67.8 ± 7.5 years) underwent clinical testing, structural MRI and fMRI at 3.0T involving repetitive right ankle and finger movements. Data were compared between individuals with absent or punctuate (n = 17) and early confluent or confluent (n = 13) WMH. Both groups did not differ in mobility or cognition data. On fMRI, subjects with severe WMH demonstrated excess activation in the pre-supplementary motor area (SMA), frontal, and occipital regions. Activation differences were noted with ankle movements only. Pre-SMA activation correlated with frontal WMH load for ankle but not finger movements. With simple ankle movements and no behavioral deficits, elderly subjects with severe WMH demonstrated pre-SMA activation, usually noted with complex tasks, as a function of frontal WMH load. This suggests compensatory activation related to disturbance of frontosubcortical circuits.

Changing topological patterns in normal aging using large-scale structural networks - Corrected Proof

Wanlin Zhu, Wei Wen, Yong He, Aihua Xia, Kaarin J. Anstey, Perminder Sachdev — 2010-08-19

Abstract: We examine normal aging from the perspective of topological patterns of structural brain networks constructed from two healthy age cohorts 20 years apart. Based on graph theory, we constructed structural brain networks using 90 cortical and subcortical regions as a set of nodes and the interregional correlations of grey matter volumes across individual brains as edges between nodes, and further analyzed the topological properties of the age-specific networks. We found that the brain structural networks of both cohorts had small-world architecture, and the older cohort (N = 374; mean age = 66.6 years, range 64–68) had lower global efficiency but higher local clustering in the brain structural networks compared with the younger cohort (N = 428; mean age = 46.7, range 44–48). The older cohort had reduced hemispheric asymmetry and lower centrality of certain brain regions, such as the bilateral hippocampus, bilateral insula, left posterior cingulated, and right Heschl gyrus, but that of the prefrontal cortex (PFC) was not different. These structural network differences may provide the basis for changes in functional connectivity and indeed cognitive function as we grow older.

A complementary diffusion tensor imaging (DTI)-histological study in a model of Huntington's disease - Corrected Proof

2010-08-19

Abstract: In vivo diffusion tensor imaging (DTI) was performed on the quinolinic acid (QUIN) rat model of Huntington's disease, together with behavioral assessment of motor deficits and histopathological characterization. DTI and histology revealed the presence of a cortical lesion in 53% of the QUIN animals (QUIN+ctx). Histologically, QUIN+ctx were distinguished from QUIN−ctx animals by increased astroglial reaction within a subregion of the caudate putamen and loss of white matter in the external capsula. Although both techniques are complementary, the quantitative character of DTI makes it possible to pick up subtle differences in tissue microstructure that are not identified with histology. DTI demonstrated differential changes of fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) in the internal and external capsula, and within a subregion of the caudate putamen. It was suggested that FA increased due to a selective loss of the subcortical connections targeted by degenerative processes at the early stage of the disease, which might turn the striatum into a seemingly more organized structure. When tissue degeneration becomes more severe, FA decreased while AD, RD and MD increased.

Association between variants in IDE-KIF11-HHEX and plasma amyloid β levels - Corrected Proof

2010-08-19

Abstract: Genetic linkage and association studies in late-onset Alzheimer’s disease (LOAD) or its endophenotypes have pointed to several regions on chromosome 10q, among these the ∼ 250 kb linkage disequilibrium (LD) block harboring the genes IDE, KIF1, and HHEX. We explored the association between variants in the genomic region harboring the IDE-KIF11-HHEX complex with plasma Aβ40 and Aβ42 levels in a case-control cohort of Caribbean Hispanics. First, we performed single marker linear regression analysis relating the individual single nucleotide polymorphisms (SNPs) with plasma Aβ40 and Aβ42 levels. Then we performed 3-SNP sliding window haplotype analyses, correcting all analyses for multiple testing. Out of 32 SNPs in this region, 3 SNPs in IDE (rs2421943, rs12264682, rs11187060) were associated with plasma Aβ40 or Aβ42 levels in single marker and haplotype analyses after correction for multiple testing. All these SNPs lie within the same LD block, and are in LD with the previously reported haplotypes. Our findings provide support for an association in the IDE region on chromosome 10q with Aβ40 and 42 levels.

Normal aging reduces motor synergies in manual pointing - Corrected Proof

Julius Verrel, Martin Lövdén, Ulman Lindenberger — 2010-08-19

Abstract: Depending upon its organization, movement variability may reflect poor or flexible control of a motor task. We studied adult age-related differences in the structure of postural variability in manual pointing using the uncontrolled manifold (UCM) method. Participants from 2 age groups (younger: 20–30 years; older: 70–80 years; 12 subjects per group) completed a total of 120 pointing trials to 2 different targets presented according to 3 schedules: blocked, alternating, and random. The age groups were similar with respect to basic kinematic variables, end point precision, as well as the accuracy of the biomechanical forward model of the arm. Following the uncontrolled manifold approach, goal-equivalent and nongoal-equivalent components of postural variability (goal-equivalent variability [GEV] and nongoal-equivalent variability [NGEV]) were determined for 5 time points of the movements (start, 10%, 50%, 90%, and end) and used to define a synergy index reflecting the flexibility/stability aspect of motor synergies. Toward the end of the movement, younger adults showed higher synergy indexes than older adults. Effects of target schedule were not reliable. We conclude that normal aging alters the organization of common multidegree-of-freedom movements, with older adults making less flexible use of motor abundance than younger adults.

Pro-oxidant diet enhances β/γ secretase-mediated APP processing in APP/PS1 transgenic mice - Corrected Proof

2010-08-19

Abstract: The etiology of Alzheimer's disease (AD) is complex with oxidative stress being a possible contributory factor to pathogenesis and disease progression. TASTPM transgenic mice expressing familial AD-associated amyloid precursor protein (APPswe) and presenilin transgenes (PS1M146V) show increased brain amyloid beta (Aβ) levels and Aβ plaques from 3 months. We tested if enhancing oxidative stress through diet would accelerate Aβ-related pathology. TASTPM were fed a pro-oxidant diet for 3 months resulting in increased brain levels of protein carbonyls, increased Nrf2, and elevated concentrations of glutathione (GSH). The diet increased both amyloid precursor protein (APP) and Aβ in the cortex of TASTPM but did not alter Aβ plaque load, presenilin 1, or β-secretase (BACE1) expression. TASTPM cortical neurons were cultured under similar pro-oxidant conditions resulting in increased levels of APP and Aβ likely as a result of enhanced β/γ secretase processing of APP. Thus, pro-oxidant conditions increase APP levels and enhance BACE1-mediated APP processing and in doing so might contribute to pathogenesis in AD.

Early onset of aging-like changes is restricted to cognitive abilities and skin structure in Cnr1−/− mice - Corrected Proof

2010-08-19

Abstract: Genetic deletion of the cannabinoid 1 (CB1) receptor leads to an early onset of learning and memory impairment. In the present study we asked whether the lack of CB1 receptors accelerates aging in general or is selective for cognitive functions. We therefore compared the onset and dynamics of age-dependent changes in social memory, locomotor activity, hearing ability, and in the histopathology of peripheral organs between wild-type and Cnr1 knockout (Cnr1−/−) mice. We observed deficits in social memory already in 3-month-old Cnr1−/− mice. In contrast, wild-type animals showed such deficits at the age of 6 months. Sensory and motor functions were similar between the genotypes. Thus, hearing loss for higher frequencies and the development of hypomotility showed a similar age-dependent course. In the periphery we detected an early onset of aging-like histological changes in the skin, but not in other organs. We conclude that the lack of CB1 receptor does not induce accelerated aging in general, but induces changes in cognitive function and in skin structure that resemble those associated with aging.

No association between DNA repair gene XRCC1 and amyotrophic lateral sclerosis - Corrected Proof

2010-08-18

Abstract: Reduced DNA repair capacity may play a role in amyotrophic lateral sclerosis (ALS) etiology. We examined the association between ALS risk and single nucleotide polymorphisms (SNPs) in the gene x-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1) utilizing data from a case-control study and 2 genome-wide association studies (the study of Irish Amyotrophic Lateral Sclerosis and the National Institute of Neurological Disorders and Stroke (NINDS) genome-wide study in Amyotrophic Lateral Sclerosis and Neurologically Normal Controls). Our results did not show any differences in the frequency of XRCC1 gene polymorphisms between ALS patients and controls free of any neurological disease.

Mitochondrial base excision repair in mouse synaptosomes during normal aging and in a model of Alzheimer's disease - Corrected Proof

Ricardo Gredilla, Lior Weissman, Jenq-Lin Yang, Vilhelm A. Bohr, Tinna Stevnsner — 2010-08-16

Abstract: Brain aging is associated with synaptic decline and synaptic function is highly dependent on mitochondria. Increased levels of oxidative DNA base damage and accumulation of mitochondrial DNA (mtDNA) mutations or deletions lead to mitochondrial dysfunction, playing an important role in the aging process and the pathogenesis of several neurodegenerative diseases. Here we have investigated the repair of oxidative base damage, in synaptosomes of mouse brain during normal aging and in an AD model. During normal aging, a reduction in the base excision repair (BER) capacity was observed in the synaptosomal fraction, which was associated with a decrease in the level of BER proteins. However, we did not observe changes between the synaptosomal BER activities of presymptomatic and symptomatic AD mice harboring mutated amyolid precursor protein (APP), Tau, and presinilin-1 (PS1) (3xTgAD). Our findings suggest that the age-related reduction in BER capacity in the synaptosomal fraction might contribute to mitochondrial and synaptic dysfunction during aging. The development of AD-like pathology in the 3xTgAD mouse model was, however, not associated with deficiencies of the BER mechanisms in the synaptosomal fraction when the whole brain was analyzed.

Implication of IL-33 gene polymorphism in Chinese patients with Alzheimer's disease - Corrected Proof

2010-08-16

Abstract: Interleukin-33 (IL-33), a newly described member of the IL-1 family, is located on chromosome 9p24, a chromosomal region of interest in Alzheimer's disease (AD) defined by many genome-wide studies. Three intronic rs1157505, rs11792633, and rs7044343 single nucleotide polymorphisms (SNPs) within IL-33 have recently been reported to be associated with risk of AD in Caucasian populations. In order to assess the involvement of the IL-33 polymorphisms in the risk of developing late onset AD (LOAD), we analyzed the genotype and allele distributions of these 3 polymorphisms in 704 Han Chinese subjects. The minor alleles of the rs11792633 polymorphism within IL-33 was significantly associated with a reduced risk of LOAD (odds ratio [OR] = 0.73, p = 0.005). Furthermore, rs11792633 polymorphism was still strongly associated with LOAD (dominant model: OR = 0.67, p = 0.015; recessive model: OR 0.57, p = 0.021; additive model: OR = 0.71, p = 0.004) after adjusting for age, gender, and the apolipoprotein E (APOE) ε4 status. Our results support the evidence that genetic variants of IL-33 affect susceptibility to LOAD in Han Chinese.

TARDBP gene mutations among Chinese patients with sporadic amyotrophic lateral sclerosis - Corrected Proof

2010-08-16

Abstract: Recently, several TARDBP mutations have been identified in sporadic amyotrophic lateral sclerosis (SALS) patients among different ethnicities. Our study aims to analyze the clinical features and mutations in the TARDBP gene among Chinese patients with SALS. One hundred sixty-five patients were studied. The mean age of onset was 50.8±12.0 years. The mean diagnostic delay was 18.8±17.1 months. A novel missense mutation (p.N378S) and a novel silent change (p.A321A) were detected in 2 male patients, respectively. A new variant of c.1098C>G in exon 6 and 2 reported variants, g.IVS1+85C>T in intron 1 and c.57A>G in exon 2, were found. The frequency of the “G” variant of c.57A>G in exon 2 and the “G” variant of c.1098C>G in exon 6 were significantly lower in the patient group than in the control (p=0.001 and p=0.024, respectively). Our findings provide first evidence that the frequency of TARDBP gene mutations is rare among Chinese SALS patients (0.61%). Several polymorphisms may influence susceptibility to amyotrophic lateral sclerosis.

Late-life hemoglobin and the incidence of Parkinson's disease - Corrected Proof

2010-08-16

Abstract: Brain iron promotes neurodegeneration in Parkinson's disease (PD). While hemoglobin (Hb) is the most abundant source of peripheral iron in humans, its relationship with PD is uncertain. This report examines the association between Hb in late life and PD incidence. From 1991 to 1993, Hb was measured in 3507 men in the Honolulu-Asia Aging Study. Men were aged 71–93 years and without PD. Participants were followed until 2001 for incident PD. Hb levels declined markedly with age. For men aged 71–75 years, 14.8% had levels < 14 g/dL versus 53.6% in those aged 86 and older (p < 0.001). During follow-up, 47 men developed PD (19.8/10,000 person-years). After age adjustment, PD incidence rose significantly from 10.3 to 34.9/10,000 person-years as Hb increased from < 14 to ≥ 16 g/dL (p = 0.024; relative hazard 3.2; 95% confidence interval, 1.2–8.9). Associations persisted after accounting for early mortality and adjustments for concomitant risk factors. While Hb declines with advancing age, evidence suggests that Hb that remains high in elderly men is associated with an increased risk of PD.

Homocysteine, neural atrophy, and the effect of caloric restriction in rhesus monkeys - Corrected Proof

2010-08-09

Abstract: Higher serum homocysteine (Hcy) levels in humans are associated with vascular pathology and greater risk for dementia, as well as lower global and regional volumes in frontal lobe and hippocampus. Calorie restriction (CR) in rhesus monkeys (Macaca mulatta) may confer neural protection against age- or Hcy-related vascular pathology. Hcy was collected proximal to a magnetic resonance imaging (MRI) acquisition in aged rhesus monkeys and regressed against volumetric and diffusion tensor imaging indexes using voxel-wise analyses. Higher Hcy was associated with lower white matter volume in pons and corpus callosum. Hcy was correlated with lower gray matter volume and density in prefrontal cortices and striatum. CR did not influence Hcy levels. However, control monkeys exhibited a strong negative correlation between Hcy and global gray matter, whereas no relationship was evident for the CR monkeys. Similar group differences were also seen across modalities in the splenium of the corpus callosum, prefrontal cortices, hippocampus, and somatosensory areas. The data suggest that CR may ameliorate the influence of Hcy on several important age-related parameters of parenchymal health.

Accumulation of resident and peripheral dendritic cells in the aging CNS - Corrected Proof

2010-08-09

Abstract: Dendritic cells (DC) are specialized antigen-presenting cells, responsible for peripheral immune responses. Recently, resident brain dendritic cells (bDC) were identified and functionally characterized in the young adult Itgax (CD11c) EYFP+ transgenic mouse brain. In the present study, we describe changes in number, phenotype, and source of bDC in the aging mouse brain. Immunohistochemistry and fluorescent activated cell sorting (FACS) analysis revealed an age-related increase in bDC with a concomitant rise in the expression of immune activation markers MHCII, CD80, and CD86. Quantification of immunolabeled bDC in the cortex, corpus callosum, and cerebellum of the aged brain revealed a 2- to 5-fold increase. In contrast, either no change or a decrease in bDC was noted in regions of adult neurogenesis. Chimeras (wild type host/EYFP+ bone marrow) suggest that the increase of EYFP+ cells in the aging brain is in part due to an accumulation of peripherally derived cells. Collectively, the numerical and phenotypic changes in bDC indicate these cells may serve as an important immune component in the functional and anatomic alterations associated with aging.

NOS3 gene rs1799983 polymorphism and incident dementia in elderly stroke survivors - Corrected Proof

2010-08-09

Abstract: Stroke is a major risk factor for the development of dementia in the elderly. It is unclear which genes influence risk of delayed dementia after stroke. We tested a single nucleotide polymorphism (SNP) in endothelial nitric oxide synthase (NOS3) gene at codon 298 (single-nucleotide polymorphism rs1799983; p.Asp298Glu) in a cohort of 355 older (>75 years) stroke survivors, who had detailed cognitive assessments from 3 months poststroke, i.e., baseline when the patients were free of dementia and subsequently at annual intervals. Of these, 253 participants were genotyped for polymorphisms in NOS3 and apolipoprotein E (APOE). Our analysis showed that homozygosity for NOS3 TT rather than the GT or GG genotype was a significant factor in the development of dementia. The presence of TT genotype increased risk of incident dementia compared with GG genotype; hazard ratio, 3.14 (95% confidence interval, 1.64–5.99; p = 0.001). We hypothesize that this may be mediated by reduction of nitric oxide production and cerebral perfusion. Our findings, if replicated widely, have implications for treatments to ameliorate cognitive decline in stroke survivors.

Ibuprofen attenuates oxidative damage through NOX2 inhibition in Alzheimer's disease - Corrected Proof

2010-08-09

Abstract: Considerable evidence points to important roles for inflammation in Alzheimer's disease (AD) pathophysiology. Epidemiological studies have suggested that long-term nonsteroidal anti-inflammatory drug (NSAID) therapy reduces the risk for Alzheimer's disease; however, the mechanism remains unknown. We report that a 9-month treatment of aged R1.40 mice resulted in 90% decrease in plaque burden and a similar reduction in microglial activation. Ibuprofen treatment reduced levels of lipid peroxidation, tyrosine nitration, and protein oxidation, demonstrating a dramatic effect on oxidative damage in vivo. Fibrillar β-amyloid (Aβ) stimulation has previously been demonstrated to induce the assembly and activation of the microglial nicotinamide adenine dinucleotide phosphate (NADPH) oxidase leading to superoxide production through a tyrosine kinase-based signaling cascade. Ibuprofen treatment of microglia or monocytes with racemic or S-ibuprofen inhibited Aβ-stimulated Vav tyrosine phosphorylation, NADPH oxidase assembly, and superoxide production. Interestingly, Aβ-stimulated Vav phosphorylation was not inhibited by COX inhibitors. These findings suggest that ibuprofen acts independently of cyclooxygenase COX inhibition to disrupt signaling cascades leading to microglial NADPH oxidase (NOX2) activation, preventing oxidative damage and enhancing plaque clearance in the brain.

Impact of changed positive and negative task-related brain activity on word-retrieval in aging - Corrected Proof

2010-08-09

Abstract: Previous functional imaging studies that compared activity patterns in older and younger adults during nonlinguistic tasks found evidence for 2 phenomena: older participants usually show more pronounced task-related positive activity in the brain hemisphere that is not dominant for the task and less pronounced negative task-related activity in temporo-parietal and midline brain regions. The combined effects of these phenomena and the impact on word retrieval, however, have not yet been assessed. We used functional magnetic resonance imaging to explore task-related positive (active task > baseline) and negative activity (baseline > active task) during semantic and phonemic verbal fluency tasks. Increased right frontal positive activity during the semantic task and reduced negative activity in the right hemisphere during both tasks was associated with reduced performance in older subjects. No substantial relationship between changes in positive and negative activity was observed in the older participants, pointing toward 2 partially independent but potentially co-occurring processes. Underlying causes of the observed functional network inefficiency during word retrieval in older adults need to be determined in the future.

Adrenal α2-adrenergic receptors in the aging normotensive and spontaneously hypertensive rat - Corrected Proof

2010-08-09

Abstract: This study investigates α2-adrenergic receptor (α2AR) mediated feedback inhibition of catecholamine release from the adrenal medulla of adult (52 weeks) and old (98 weeks) spontaneously hypertensive rats (SHR) and normotensive controls Wistar Kyoto (WKY) rats. Adrenal epinephrine content as well as the spontaneous and the nicotinic-evoked release of epinephrine were similar between adult SHR and WKY rats. Aging produced a significant reduction in epinephrine synthesis in WKY rats. In contrast, in SHR aging produced a significant increase in epinephrine release without significant changes in epinephrine synthesis. The α2AR agonist medetomidine abolished (80–90% inhibition) the nicotinic-evoked release of epinephrine in adult SHR and WKY rats. With aging, this effect was unaltered in WKY rats but was significantly decreased in SHR (30% inhibition). Adrenal α2AAR mRNA levels were significantly reduced in old SHR compared with age matched WKY rats. In conclusion, in aging the α2AR mediated feedback inhibition of epinephrine release from the adrenal medulla is preserved in WKY rats but compromised in SHR, resulting in increased epinephrine release.

Association of serotonin and dopamine gene pathways with behavioral subphenotypes in dementia - Corrected Proof

2010-08-05

Abstract: Genetic association studies investigating the association between genes of serotonergic and dopaminergic systems and behavioral and psychological symptoms in dementia (BPSD) are contradictory. We have utilized 1008 probable Alzheimer's disease (AD) patients from the UK and used the 12-item Neuropsychiatric Inventory. We applied a multiple indicators-multiple causes (MIMIC) approach to investigate the effect of 11 polymorphisms on the 4 behavioral subphenotypes “psychosis”, “moods”, “agitation”, and “behavioural dyscontrol”. Significant associations were observed between the serotonin transporter gene (SERT) polymorphism STin2 and “psychosis”; the dopamine transporter gene (DAT) 3′ variable number tandem repeats (VNTR) and “agitation”; and the dopamine receptor 4 (DRD4) VNTR and “moods” factors. Direct associations were identified between the dopamine receptor 3 (DRD3) BalI polymorphism and depression; the dopamine receptor 1 (DRD1) and dopamine transporter gene 3′ VNTR polymorphisms and aberrant motor behavior; the DRD4 VNTR and sleep disturbances; and the SERT gene VNTR 5HTTLPR and apathy items. Significant interactions observed between polymorphisms suggested epistatic effects and interactions between polymorphisms and medications highlighted potential treatment response. This multiple indicators multiple causes (MIMIC) model efficiently captured the complexity of the interrelations between genetic variation, behavioral symptoms, and clinical variables.

Dynamic changes in PET amyloid and FDG imaging at different stages of Alzheimer's disease - Corrected Proof

2010-08-05

Abstract: In this study 5 patients with mild cognitive impairment (MCI) and 9 Alzheimer’s disease (AD) patients underwent respectively 3- and 5-year follow-uppositron emission tomography (PET) studies with N-methyl [11C] 2-(4-methylaminophenyl)-6-hydroxy-benzothiazole (11C-PIB) and 18F-fluorodeoxyglucose(18F-FDG) to understand the time courses in AD disease processes. Significant increase in PIB retention as well as decrease inregional cerebral metabolic rate of glucose (rCMRglc) was observed at group level in the MCI patients while no significant change was observed incognitive function. At group level the AD patients showed unchanged high PIB retention at 5-year follow-up compared with baseline. At theindividual level, increased, stable, and decreased PIB retention were observed while disease progression was reflected in significant decrease inrCMRglc and cognition. In conclusion, after a long-term follow-up with PET, we observed an increase in fibrillar amyloid load in MCI patientsfollowed by more stable level in clinical AD patients. The rCMRglc starts to decline in MCI patients and became more pronounced in clinical stagewhich related to continuous decline in cognition.

Prefrontal mediation of age differences in cognitive reappraisal - Corrected Proof

Philipp C. Opitz, Lindsay C. Rauch, Douglas P. Terry, Heather L. Urry — 2010-08-02

Abstract: Despite cognitive and physical declines, it has been suggested that older adults remain able to regulate their emotions effectively. However, whether this is true for all emotion regulation processes has not been established. We hypothesized that cognitive reappraisal, a form of emotion regulation requiring intact cognitive control ability, may be compromised in older age, and that this age difference would be mediated by reduced activation in prefrontal cortex (PFC). Sixteen younger and 15 older adults used gaze-directed reappraisal to increase and decrease emotion in response to unpleasant pictures. This was compared with simply viewing the pictures. Relative to younger adults, older adults were less successful using reappraisal to decrease unpleasant emotion but more successful using reappraisal to increase unpleasant emotion. They also exhibited reduced activation in dorsomedial and left ventrolateral prefrontal cortex. Importantly, activation in these regions differentially mediated the effect of age on emotion. This pattern confirms the importance of cognitive control in reappraising unpleasant situations and suggests that older age may (but does not always) confer effective emotion regulation.

Engulfment adapter PTB domain containing 1 interacts with and affects processing of the amyloid-β precursor protein - Corrected Proof

2010-08-02

Abstract: Previous studies identified engulfment adapter phosphotyrosine binding (PTB) domain containing 1 (GULP1) as an NPXY-motif interactor of low-density lipoprotein receptor-related protein 1 (LRP1) and suggested a potential relevance in Alzheimer's disease (AD). Since AD associated proteins amyloid-β A4 precursor protein (APP) and LRP1 were shown to interact with the PTB domain of Fe65 and several other adapters via their intracellular NPXY-motifs, we examined a possible interaction of GULP1 PTB domain with the YENPTY-motif of APP. Here we demonstrate that GULP1 is present in human hippocampal and neocortical neurons. Confocal live cell imaging revealed that coexpressed and endogenous GULP1 colocalizes with APP in the Golgi and endoplasmic reticulum. Analysis of the interacting domains by co-immunoprecipitation of point and deletion mutants revealed that the interaction depends on the PTB domain of GULP1 and the YENPTY-motif of APP. Coexpression of GULP1 affected APP cell surface localization and suppressed generation of Aβ40/42 and sAPPα. Taken together, these data identify GULP1 as a novel neuronal APP interacting protein that alters trafficking and processing of APP.

BDNF upregulation rescues synaptic plasticity in middle-aged ovariectomized rats - Corrected Proof

2010-08-02

Abstract: Brain-derived neurotrophic factor (BDNF) has emerged as a possible broad-spectrum treatment for the plasticity losses found in rodent models of human conditions associated with memory and cognitive deficits. We have tested this strategy in the particular case of ovariectomy. The actin polymerization in spines normally found after patterned afferent stimulation was greatly reduced, along with the stabilization of long-term potentiation, in hippocampal slices prepared from middle-aged ovariectomized rats. Both effects were fully restored by a 60-minute infusion of 2 nM BDNF. Comparable rescue results were obtained after elevating endogenous BDNF protein levels in hippocampus with 4 daily injections of a short half-life ampakine (positive modulator of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate [AMPA]-type glutamate receptors). These results provide the first evidence that minimally invasive, mechanism-based drug treatments can ameliorate defects in spine plasticity caused by depressed estrogen levels.

HSV-1 promotes Ca2+-mediated APP phosphorylation and Aβ accumulation in rat cortical neurons - Corrected Proof

2010-08-02

Abstract: Epidemiological and experimental findings suggest that chronic infection with Herpes simplex virus type 1 (HSV-1) may be a risk factor for Alzheimer's disease (AD), but the molecular mechanisms underlying this association have not been fully identified. We investigated the effects of HSV-1 on excitability and intracellular calcium signaling in rat cortical neurons and the impact of these effects on amyloid precursor protein (APP) processing and the production of amyloid-β peptide (Aβ). Membrane depolarization triggering firing rate increases was observed shortly after neurons were challenged with HSV-1 and was still evident 12 hours postinfection. These effects depended on persistent sodium current activation and potassium current inhibition. The virally induced hyperexcitability triggered intracellular Ca2+ signals that significantly increased intraneuronal Ca2+ levels. It also enhanced activity- and Ca2+-dependent APP phosphorylation and intracellular accumulation of Aβ42. These findings indicate that HSV-1 causes functional changes in cortical neurons that promote APP processing and Aβ production, and they are compatible with the co-factorial role for HSV-1 in the pathogenesis of AD suggested by previous findings.

Nuclear localization sequence of FUS and induction of stress granules by ALS mutants - Corrected Proof

2010-08-02

Abstract: Mutations in fused in sarcoma (FUS) have been reported to cause a subset of familial amyotrophic lateral sclerosis (ALS) cases. Wild-type FUS is mostly localized in the nuclei of neurons, but the ALS mutants are partly mislocalized in the cytoplasm and can form inclusions. We demonstrate that the C-terminal 32 amino acid residues of FUS constitute an effective nuclear localization sequence (NLS) as it targeted beta-galactosidase (LacZ, 116 kDa) to the nucleus. Deletion of or the ALS mutations within the NLS caused cytoplasmic mislocalization of FUS. Moreover, we identified the poly-A binding protein (PABP1), a stress granule marker, as an interacting partner of FUS. Large PABP1-positive cytoplasmic foci (i.e. stress granules) colocalized with the mutant FUS inclusions but were absent in wild-type FUS-expressing cells. Processing bodies, which are functionally related to stress granules, were adjacent to but not colocalized with the mutant FUS inclusions. Our results suggest that the ALS mutations in FUS NLS can impair FUS nuclear localization, induce cytoplasmic inclusions and stress granules, and potentially perturb RNA metabolism.

Estrogen receptor alpha gene variants are associated with Alzheimer's disease - Corrected Proof

2010-08-02

Abstract: The present research is aimed at assessing the role of 3 estrogen receptor alpha (ESR1) gene variants in late onset Alzheimer's disease (AD) susceptibility. One thousand one hundred thirteen unrelated late onset sporadic AD patients, 1109 healthy controls and 121 neurologically healthy elderly controls were used to carry out case-control genetic association studies with ESR1 rs3844508, rs2234693, and ESR1 noncoding deletion 1 (ESR1-NCD1) polymorphisms. Thirty-five healthy male samples were used for molecular analyses. The rs2234693 polymorphism is associated with AD in our population (odds ratio [OR], 1.29; p = 0.008). The rs3844508 marker confers protection against AD in males (OR, 0.57; p = 0.001) and the deletion ESR1-NCD1 is a risk factor for AD in women (OR, 1.67; p < 0.001). Molecular analyses on ESR1-NCD1 indicate that this deletion confers a higher response to estradiol activity on ESR1 receptor and it is also associated with differential expression of ESR1 isoforms. Our results support the involvement of ESR1 gene in AD and point to the existence of sexual dimorphism for ESR1 markers. In addition, carriers of ESR1-NCD1 deletion could overrespond to estradiol action.

Large-scale screening of TARDBP mutation in amyotrophic lateral sclerosis in Japanese - Corrected Proof

2010-08-02

Abstract: Mutations in TARDBP encoding TDP (TAR DNA binding protein)-43 have been reported in familial and sporadic amyotrophic lateral sclerosis (ALS), but mostly in Caucasians. In other ethnic groups, four types of mutations are found in familial ALS. In sporadic ALS, the TARDBP mutations frequency is low in Caucasians (0–5%) and no mutation has been found in other ethnic groups. To examine spectrum of TARDBP mutations and its frequency in Japanese, we screened the TARDBP mutation in 721 Japanese ALS by direct sequencing. We identified a novel mutation, c.1069G > A (p.Gly357Ser) and a known mutation in sporadic ALS. One patient was homozygous for p.Gly357Ser, which was the first for TARDBP mutation. Our study showed that TARDBP mutations also occur in non-Caucasian sporadic ALS. The estimated frequency of the TARDBP mutation in sporadic ALS is 0.29% in Japanese. The mutation frequency in familial ALS in Japanese is also similar to that in Caucasian, and is ∼10 times higher than that in Japanese sporadic ALS.

Aluminum induces neurodegeneration and its toxicity arises from increased iron accumulation and reactive oxygen species (ROS) production - Corrected Proof

Zhihao Wu, Yumei Du, Hua Xue, Yongsheng Wu, Bing Zhou — 2010-08-02

Abstract: The neurotoxicity of aluminum (Al) − the most abundant metal element on earth − has been known for years. However, the mechanism of Al-induced neurodegeneration and its relationship to Alzheimer's disease are still controversial. In particular, in vivo functional data are lacking. In a Drosophila model with chronic dietary Al overloading, general neurodegeneration and several behavioral changes were observed. Al-induced neurodegeneration is independent of β-amyloid or tau-associated toxicity, suggesting they act in different molecular pathways. Interestingly, Drosophila frataxin (dfh), which causes Friedreich's ataxia if mutated in humans, displayed an interacting effect with Al, suggesting Friedreich's ataxia patients might be more susceptible to Al toxicity. Al-treated flies accumulated large amount of iron and reactive oxygen species (ROS), and exhibited elevated SOD2 activity. Genetic and pharmacological efforts to reduce ROS or chelate excess Fe significantly mitigated Al toxicity. Our results indicate that Al toxicity is mediated through ROS production and iron accumulation and suggest a remedial route to reduce toxicity due to Al exposure.

Cellular stress from excitatory neurotransmission contributes to cholesterol loss in hippocampal neurons aging in vitro - Corrected Proof

Alejandro O. Sodero, Carina Weissmann, Maria Dolores Ledesma, Carlos G. Dotti — 2010-07-22

Abstract: After approximately 3 weeks in vitro, hippocampal neurons present many of the typical hallmarks accompanying neuronal aging in vivo, including accumulation of reactive oxygen species (ROS), lipofuscin granules, heterochromatic foci, and activation of the Jun N-terminal protein kinase (pJNK) and p53/p21 pathways. In addition, hippocampal neurons in vitro undergo a gradual loss of cholesterol, which is important for the activation of the prosurvival tyrosine kinase receptor TrkB. Here, we used the hippocampal in vitro system to investigate the possible cause of age-accompanying cholesterol loss. We report that cholesterol loss during in vitro aging is paralleled by upregulation and translocation to the neuronal surface of cholesterol-24-hydroxylase (Cyp46), the enzyme responsible for cholesterol removal from neurons. Chronic reduction of electrical activity diminished cholesterol loss in aged neurons and precluded the upregulation of cholesterol-24-hydroxylase. In agreement with a cause-effect relationship, stimulation of excitatory neurotransmission in young neurons led to cholesterol loss. Mechanistically, N-methyl-D-aspartate (NMDA)-mediated excitatory neurotransmission leads to cholesterol loss through generation of reactive oxygen species derived from the activation of the stress-responsive enzyme NADPH oxidase. Supporting the relevance of the in vitro data, reduced cholesterol was also detected in synaptic membranes from old mice brains. Furthermore, excitatory neurotransmission via the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase pathway induced cholesterol loss in purified brain synaptosomes. The current studies highlight excitatory neurotransmission as 1 of the mechanisms involved in cholesterol loss during aging.

AGEs/RAGE complex upregulates BACE1 via NF-κB pathway activation - Corrected Proof

2010-07-20

Abstract: Although the pathogenesis of sporadic Alzheimer disease (AD) is not clearly understood, it is likely dependent on several age-related factors. Diabetes is a risk factor for AD, and multiple mechanisms connecting the 2 diseases have been proposed. Hyperglycemia enhances the formation of advanced glycation end products (AGEs) that result from the auto-oxidation of glucose and fructose. The interaction of AGEs with their receptor, named RAGE, elicits the formation of reactive oxygen species that are also believed to be an early event in AD pathology. To investigate a functional link between the disorders diabetes and AD, the effect of 2 AGEs, pentosidine and glyceraldehydes-derived pyridinium (GLAP), was studied on BACE1 expression both in vivo, in streptozotocin treated rats, and in vitro in differentiated neuroblastoma cells. We showed that pentosidine and GLAP were able to upregulate BACE1 expression through their binding with RAGE and the consequent activation of NF-κB. In addition, both pentosidine and GLAP were found to be increased in the brain in sporadic AD patients. Our findings demonstrate that activation of the AGEs/RAGE axis, by upregulating the key enzyme for amyloid-β production, provides a pathologic link between diabetes mellitus and AD.

LRP1 mediates bidirectional transcytosis of amyloid-β across the blood-brain barrier - Corrected Proof

2010-07-15

Abstract: According to the “amyloid hypothesis”, the amyloid-β (Aβ) peptide is the toxic intermediate driving Alzheimer's disease (AD) pathogenesis. Recent evidence suggests that the low density lipoprotein receptor-related protein 1 (LRP1) transcytoses Aβ out of the brain across the blood-brain barrier (BBB). To provide genetic evidence for LRP1-mediated transcytosis of Aβ across the BBB we analyzed Aβ transcytosis across primary mouse brain capillary endothelial cells (pMBCECs) derived from wild-type and LRP1 knock-in mice. Here, we show that pMBCECs in vitro express functionally active LRP1. Moreover, we demonstrate that LRP1 mediates transcytosis of [125I]-Aβ1–40 across pMBCECs in both directions, whereas no role for LRP1-mediated Aβ degradation was detected. Analysis of [125I]-Aβ1–40 transport across pMBCECs generated from mice harboring a knock-in mutation in the NPxYxxL endocytosis/sorting domain of endogenous LRP1 revealed a reduced Aβ clearance from brain-to-blood and blood-to-brain compared with wild-type derived pMBCECs. Therefore, for the first time, we present genetic evidence that LRP1 modulates the pathogenic actions of soluble Aβ in the brain by clearing Aβ across the BBB.

Longitudinal genetic analysis of brain volumes in normal elderly male twins - Corrected Proof

2010-07-15

Abstract: This study investigated the role of genetic and environmental influences on individual differences in brain volumes measured at 2 time points in normal elderly males from the National Heart, Lung, and Blood Institute Twin Study. The magnetic resonance imaging (MRI) scans were conducted 4 years apart on 33 monozygotic and 33 dizygotic male twin pairs, aged 68 to 77 years when first scanned. Volumetric measures of total brain and total cerebrospinal fluid were significantly heritable at baseline (over 70%). For both volumes genetic influences at follow-up were entirely accounted for by genetic influences at baseline, suggesting that the same genetic factors influence variability in brain volume at each time of assessment. Variability in 4-year volume change was due to shared and individual-specific environmental influences. There was little evidence for heritable influences on change measures. These results suggest that variation in longitudinal change of some brain volume measures may have different underlying genetic and environmental architecture from variation in repeat cross-sectional measures, which could have implications for intervention strategies for age-related illness associated with brain morphology. The results of this study are discussed in the context of the small sample size and associated limitations of statistical power.

MicroRNA-16 targets amyloid precursor protein to potentially modulate Alzheimer's-associated pathogenesis in SAMP8 mice - Corrected Proof

2010-07-12

Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder mainly characterized by amyloid-beta (Aβ) deposition and neurofibrillary tangles (NFTs). The abnormal enrichment of amyloid protein precursor (APP) leads to a high risk of AD. One of the plausible age-associated AD animal models, senescence-accelerated mouse prone 8 (SAMP8), have age-related learning and memory deficits. We found APP protein significantly increased in the hippocampus of aged SAMP8 mice. The 20 to 25 nucleotide (nt) tiny regulators, known as micro ribonucleic acids (miRNAs), have been found to play crucial roles in neurodegenerative diseases. Here, we examined the post-transcriptional regulation mechanism of APP mediated by micro ribonucleic acids and found that miR-16 was one of the post-transcriptional regulators of APP in SAMP8 mice. Overexpression of miR-16, both in vitro and in vivo, led to reduced APP protein expression. Furthermore, miR-16 and APP displayed complementary expression patterns in SAMP8 mice and BALb/c mice embryos. Taken together, these findings demonstrate that APP is a target of miR-16 and the abnormally low expression of miR-16 could potentially lead to APP protein accumulation in AD mice.

Widespread Lewy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations - Corrected Proof

2010-07-12

Abstract: The 2 major types of neurodegeneration with brain iron accumulation (NBIA) are the pantothenate kinase type 2 (PANK2)-associated neurodegeneration (PKAN) and NBIA2 or infantile neuroaxonal dystrophy (INAD) due to mutations in the phospholipase A2, group VI (PLA2G6) gene. We have recently demonstrated clinical heterogeneity in patients with mutations in the PLA2G6 gene by identifying a poorly defined subgroup of patients who present late with dystonia and parkinsonism. We report the clinical and genetic features of 7 cases with PLA2G6 mutations. Brain was available in 5 cases with an age of death ranging from 8 to 36 years and showed widespread alpha-synuclein-positive Lewy pathology, which was particularly severe in the neocortex, indicating that the Lewy pathology spread corresponded to Braak stage 6 and was that of the “diffuse neocortical type”. In 3 cases there was hyperphosphorylated tau accumulation in both cellular processes as threads and neuronal perikarya as pretangles and neurofibrillary tangles. Later onset cases tended to have less tau involvement but still severe alpha-synuclein pathology. The clinical and neuropathological features clearly represent a link between PLA2G6 and parkinsonian disorders.

Age-related changes in sleep in inbred mice are genotype dependent - Corrected Proof

Sibah Hasan, Yves Dauvilliers, Valérie Mongrain, Paul Franken, Mehdi Tafti — 2010-07-12

Abstract: Aging produces major changes in sleep structure and intensity which might be linked to cognitive impairment in the elderly. In this study, the genetic contribution to age-related changes in sleep was assessed in three inbred mouse strains of various ages. Baseline sleep and the response to 6 hours sleep deprivation (SD) achieved by gentle handling were quantified in young, middle-aged, and older male mice using electroencephalography. Total sleep time initially increased with age but then decreased in the oldest group mainly due to changes in sleep duration during the active phase. The effect of age on electroencephalographic (EEG) delta power depends on genotype and sleep pressure level with SD increasing the age-related differences. The strong effect of age upon the spectral profile of the different behavioral states was modulated by genetic background. Overall, our results suggest that sleep pressure can modulate the effect of age, that most sleep variables do not monotonically change with age in contrast to previous reports in humans and other species, and that genetic factors have a major impact on the aging processes affecting sleep.

Sex differences in the association of the apolipoprotein E epsilon 4 allele with incidence of dementia, cognitive impairment, and decline - Corrected Proof

2010-07-12

Abstract: We examined longitudinal associations between the apolipoprotein E ε4 allele (ApoE4+ status) and several cognitive outcomes and tested effect modification by sex. Data on 644 non-Hispanic Caucasian adults, from the Baltimore Longitudinal Study of Aging (BLSA) were used. Dementia onset, cognitive impairment and decline were assessed longitudinally. After 27.5 years median follow-up, 113 participants developed dementia. ApoE4+ predicted dementia significantly (hazard ratio [HR] = 2.89; 95% confidence interval [CI], 1.93–4.33), with nonsignificant sex differences. Taking all time points for predicting cognition, women had significantly stronger positive associations than men between ApoE4+ status and impairment or decline on the California Verbal Learning Test (CVLT; delayed recall and List A total recall) and on Verbal Fluency Test-Categories. This ApoE4 × sex interaction remained significant with Bonferroni correction only for CVLT-delayed recall. Taking time points prior to dementia for cognitive predictions, the positive association between impairment in CVLT-delayed recall and ApoE4+ status remained stronger among women, though only before Bonferroni correction. While ApoE4+ status appears to be a sex neutral risk factor for dementia, its association with verbal memory and learning decline and impairment was stronger among women.

A meta-analysis of diffusion tensor imaging in mild cognitive impairment and Alzheimer's disease - Corrected Proof

2010-07-12

Abstract: We reviewed case-control studies of diffusion tensor imaging (DTI) in patients with Alzheimer's dementia (AD) and mild cognitive impairment (MCI), in order to establish the relative severity and location of white matter microstructural changes. EMBASE and MEDLINE were searched using the keywords, ([“diffusion tensor”] and [“Alzheimer*” or “mild cognitive impairment”]), as were reference lists of relevant papers. Forty-one diffusion tensor imaging studies contained data that were suitable for inclusion. Group means and standard deviations for fractional anisotropy and mean diffusivity, or p values from 2-sample tests, were extracted and pooled, using standard methods of meta-analysis and metaregression. Fractional anisotropy was decreased in AD in all regions except parietal white matter and internal capsule, while patients with MCI had lower values in all white matter regions except parietally and occipitally. Mean diffusivity was increased in AD in all regions, and in MCI in all but occipital and frontal regions.

Motor deficits, neuron loss, and reduced anxiety coinciding with axonal degeneration and intraneuronal Aβ aggregation in the 5XFAD mouse model of Alzheimer's disease - Corrected Proof

Sadim Jawhar, Anna Trawicka, Carolin Jenneckens, Thomas A. Bayer, Oliver Wirths — 2010-07-12

Abstract: In the present report, we extend previous findings in the 5XFAD mouse model and demonstrate that these mice develop an age-dependent motor phenotype in addition to working memory deficits and reduced anxiety levels as demonstrated in an elevated plus maze task. Employing a variety of N- and C-terminal specific Aβ antibodies, abundant intraneuronal and plaque-associated pathology, including accumulation of pyroglutamate Aβ, was observed as early as the age of 3 months. Using unbiased stereology, we demonstrate that the 5XFAD mice develop a significant selective neuron loss in layer 5 of the cortex, leaving the overall neuron number of the total frontal cortex and hippocampus unaffected. This observation coincides with the accumulation of intraneuronal Aβ peptides only in cortical Layer 5, but not in CA1, despite comparable APP expression levels. The motor phenotype correlates with abundant spinal cord pathology, as demonstrated by abundant intraneuronal Aβ accumulation and extracellular plaque deposition. In addition, comparable to the APP/PS1KI mouse model, 5XFAD mice develop an age-dependent axonopathy likely contributing to the behavioral deficits.

A de novo missense mutation of the FUS gene in a “true” sporadic ALS case - Corrected Proof

2010-07-05

Abstract: Mutations in the Cu/Zn superoxide dismutase (SOD1), transactive response (TAR)-DNA binding protein (TARDBP) and fused in sarcoma (FUS) genes account for approximately 1 third of familial amyotrophic lateral sclerosis (ALS) cases. Mutations in these genes have been found in 1% to 2% of apparently sporadic cases. We present the first case of an ALS patient carrying a de novo missense mutation of the FUS gene (c.1561C>T, p.R521C). This report highlights the importance of screening ALS patients, both familial and sporadic, for FUS mutations and also suggests that de novo mutations is a relevant mechanism underlying sporadic neurodegenerative disease.

Neuroprotection of kaempferol by autophagy in models of rotenone-mediated acute toxicity: possible implications for Parkinson's disease - Corrected Proof

2010-07-02

Abstract: This study aims to elucidate the processes underlying neuroprotection of kaempferol in models of rotenone-induced acute toxicity. We demonstrate that kaempferol, but not quercetin, myricetin or resveratrol, protects SH-SY5Y cells and primary neurons from rotenone toxicity, as a reduction of caspases cleavage and apoptotic nuclei are observed. Reactive oxygen species (ROS) levels and mitochondrial carbonyls decrease significantly. Mitochondrial network, transmembrane potential and oxygen consumption are also deeply preserved. We demonstrate that the main event responsible for the kaempferol-mediated antiapoptotic and antioxidant effects is the enhancement of mitochondrial turnover by autophagy. Indeed, fluorescence and electron microscopy analyses show an increase of the mitochondrial fission rate and mitochondria-containing autophagosomes. Moreover, the autophagosome-bound microtubule-associated protein light chain-3 (LC3-II) increases during kaempferol treatment and chemical/genetic inhibitors of autophagy abolish kaempferol protective effects. Autophagy affords protection also toward other mitochondrial toxins (1-methyl-4-phenyilpiridinium, paraquat) used to reproduce the typical features of Parkinson's disease (PD), but is inefficient against apoptotic stimuli not directly affecting mitochondria (H2O2, 6-hydroxydopamine, staurosporine). Striatal glutamatergic response of rat brain slices is also preserved by kaempferol, suggesting a more general protection of kaempferol in Parkinson's disease. Overall, the data provide further evidence for kaempferol to be identified as an autophagic enhancer with potential therapeutic capacity.