Genetic association of CDC2 with cerebrospinal fluid tau in Alzheimer's disease

We have recently reported that a polymorphism in the cell division cycle (CDC2) gene, designated Ex6 + 7I/D, is associated with Alzheimer's disease (AD). The CDC2 gene is located on chromosome 10q21.1 close to the marker D10S1225 linked to AD. Active cdc2 accumulates in neurons containing neurofibrillary tangles (NFT), a process that can precede the formation of NFT. Therefore, CDC2 is a promising candidate susceptibility gene for AD. We investigated the possible effects of the CDC2 polymorphism on cerebrospinal fluid (CSF) biomarkers in AD patients. CDC2 genotypes were evaluated in relation to CSF protein levels of total tau, phospho-tau and beta-amyloid (1-42) in AD patients and control individuals, and in relation to the amount of senile plaques and NFT in the frontal cortex and in the hippocampus in patients with autopsy-proven AD and controls. The CDC2 Ex6 + 7I allele was associated with a gene dose-dependent increase of CSF total tau levels (F-2,F- 626 = 7.0, p = 0.001) and the homozygous CDC2Ex6 +7II genotype was significantly more frequent among AD patients compared to controls (p = 0.006, OR = 1.57, 95% CI 1.13-2.17). Our results provide further evidence for an involvement of cdc2 in the pathogenesis of AD. Copyright (C) 2005 S. Karger AG, Basel

Quantification of myelin loss in frontal lobe white matter in vascular dementia, Alzheimer's disease, and dementia with Lewy bodies

The aim of this study was to characterize myelin loss as one of the features of white matter abnormalities across three common dementing disorders. We evaluated post-mortem brain tissue from frontal and temporal lobes from 20 vascular dementia (VaD), 19 Alzheimer’s disease (AD) and 31 dementia with Lewy bodies (DLB) cases and 12 comparable age controls. Images of sections stained with conventional luxol fast blue were analysed to estimate myelin attenuation by optical density. Serial adjacent sections were then immunostained for degraded myelin basic protein (dMBP) and the mean percentage area containing dMBP (%dMBP) was determined as an indicator of myelin degeneration. We further assessed the relationship between dMBP and glutathione S-transferase (a marker of mature oligodendrocytes) immunoreactivities. Pathological diagnosis significantly affected the frontal but not temporal lobe myelin attenuation: myelin density was most reduced in VaD compared to AD and DLB, which still significantly exhibited lower myelin density compared to ageing controls. Consistent with this, the degree of myelin loss was correlated with greater %dMBP, with the highest %dMBP in VaD compared to the other groups. The %dMBP was inversely correlated with the mean size of oligodendrocytes in VaD, whereas it was positively correlated with their density in AD. A two-tier regression model analysis confirmed that the type of disorder (VaD or AD) determines the relationship between %dMBP and the size or density of oligodendrocytes across the cases. Our findings, attested by the use of three markers, suggest that myelin loss may evolve in parallel with shrunken oligodendrocytes in VaD but their increased density in AD, highlighting partially different mechanisms are associated with myelin degeneration, which could originate from hypoxic–ischaemic damage to oligodendrocytes in VaD whereas secondary to axonal degeneration in AD

Nuclear poly(ADP-ribose) activity is a therapeutic target in amyotrophic lateral sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a devastating and fatal motor neuron disease. Diagnosis typically occurs in the fifth decade of life and the disease progresses rapidly leading to death within ~ 2–5 years of symptomatic onset. There is no cure, and the few available treatments offer only a modest extension in patient survival. A protein central to ALS is the nuclear RNA/DNA-binding protein, TDP-43. In > 95% of ALS patients, TDP-43 is cleared from the nucleus and forms phosphorylated protein aggregates in the cytoplasm of affected neurons and glia. We recently defined that poly(ADP-ribose) (PAR) activity regulates TDP-43-associated toxicity. PAR is a posttranslational modification that is attached to target proteins by PAR polymerases (PARPs). PARP-1 and PARP-2 are the major enzymes that are active in the nucleus. Here, we uncovered that the motor neurons of the ALS spinal cord were associated with elevated nuclear PAR, suggesting elevated PARP activity. Veliparib, a small-molecule inhibitor of nuclear PARP-1/2, mitigated the formation of cytoplasmic TDP-43 aggregates in mammalian cells. In primary spinal-cord cultures from rat, Veliparib also inhibited TDP-43-associated neuronal death. These studies uncover that PAR activity is misregulated in the ALS spinal cord, and a small-molecular inhibitor of PARP-1/2 activity may have therapeutic potential in the treatment of ALS and related disorders associated with abnormal TDP-43 homeostasis

Post-mortem assessment in vascular dementia: advances and aspirations.

BACKGROUND: Cerebrovascular lesions are a frequent finding in the elderly population. However, the impact of these lesions on cognitive performance, the prevalence of vascular dementia, and the pathophysiology behind characteristic in vivo imaging findings are subject to controversy. Moreover, there are no standardised criteria for the neuropathological assessment of cerebrovascular disease or its related lesions in human post-mortem brains, and conventional histological techniques may indeed be insufficient to fully reflect the consequences of cerebrovascular disease. DISCUSSION: Here, we review and discuss both the neuropathological and in vivo imaging characteristics of cerebrovascular disease, prevalence rates of vascular dementia, and clinico-pathological correlations. We also discuss the frequent comorbidity of cerebrovascular pathology and Alzheimer's disease pathology, as well as the difficult and controversial issue of clinically differentiating between Alzheimer's disease, vascular dementia and mixed Alzheimer's disease/vascular dementia. Finally, we consider additional novel approaches to complement and enhance current post-mortem assessment of cerebral human tissue. CONCLUSION: Elucidation of the pathophysiology of cerebrovascular disease, clarification of characteristic findings of in vivo imaging and knowledge about the impact of combined pathologies are needed to improve the diagnostic accuracy of clinical diagnoses

Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease.

International audienceRecently, several genome wide association studies (GWAS) have led to the discovery of 9 new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches.. We performed a genome wide haplotype association (GWHA) study in the EADI1 study (n=2,025 AD cases and 5,328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2,820 AD cases and 6,356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case-control studies (5,093 AD cases and 4,061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analysed (OR=1.68, 95% CI 1.43- 1.96; p=1.1x10-10). We finally searched for association between SNPs within the FRMD4A locus and Ab plasma concentrations in three independent non demented populations (n=2,579). We reported that polymorphisms were associated with plasma Ab42/Ab40 ratio (best signal, p=5.4x10-7). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD

A comparative analysis of the information content in long and short SAGE libraries

BACKGROUND: Serial Analysis of Gene Expression (SAGE) is a powerful tool to determine gene expression profiles. Two types of SAGE libraries, ShortSAGE and LongSAGE, are classified based on the length of the SAGE tag (10 vs. 17 basepairs). LongSAGE libraries are thought to be more useful than ShortSAGE libraries, but their information content has not been widely compared. To dissect the differences between these two types of libraries, we utilized four libraries (two LongSAGE and two ShortSAGE libraries) generated from the hippocampus of Alzheimer and control samples. In addition, we generated two additional short SAGE libraries, the truncated long SAGE libraries (tSAGE), from LongSAGE libraries by deleting seven 5' basepairs from each LongSAGE tag. RESULTS: One problem that occurred in the SAGE study is that individual tags may have matched to multiple different genes – due to the short length of a tag. We found that the LongSAGE tag maps up to 15 UniGene clusters, while the ShortSAGE and tSAGE tags map up to 279 UniGene clusters. Both long and short SAGE libraries exhibit a large number of orphan tags (no gene information in UniGene), implying the limitation of the UniGene database. Among 100 orphan LongSAGE tags, the complete sequences (17 basepairs) of nine orphan tags match to 17 genomic sequences; four of the orphan tags match to a single genomic sequence. Our data show the potential to resolve 4–9% of orphan LongSAGE tags. Finally, among 400 tSAGE tags showing significant differential expression between AD and control, 79 tags (19.8%) were derived from multiple non-significant LongSAGE tags, implying the false positive results. CONCLUSION: Our data show that LongSAGE tags have high specificity in gene mapping compared to ShortSAGE tags. LongSAGE tags show an advantage over ShortSAGE in identifying novel genes by BLAST analysis. Most importantly, the chances of obtaining false positive results are higher for ShortSAGE than LongSAGE libraries due to their specificity in gene mapping. Therefore, it is recommended that the number of corresponding UniGene clusters (gene or ESTs) of a tag for prioritizing the significant results be considered

Cerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes cortical microinfarcts

Cortical microinfarcts (CMIs) observed in brains of patients with Alzheimer’s disease tend to be located close to vessels afflicted with cerebral amyloid angiopathy (CAA). CMIs in Alzheimer’s disease are preferentially distributed in the arterial borderzone, an area most vulnerable to hypoperfusion. However, the causal association between CAA and CMIs remains to be elucidated. This study consists of two parts: (1) an observational study using postmortem human brains (n = 31) to determine the association between CAA and CMIs, and (2) an experimental study to determine whether hypoperfusion worsens CAA and induces CMIs in a CAA mouse model. In postmortem human brains, the density of CMIs was 0.113/cm2 in mild, 0.584/cm2 in moderate, and 4.370/cm2 in severe CAA groups with a positive linear correlation (r = 0.6736, p < 0.0001). Multivariate analysis revealed that, among seven variables (age, disease, senile plaques, neurofibrillary tangles, CAA, atherosclerosis and white matter damage), only the severity of CAA was a significant multivariate predictor of CMIs (p = 0.0022). Consistent with the data from human brains, CAA model mice following chronic cerebral hypoperfusion due to bilateral common carotid artery stenosis induced with 0.18-mm diameter microcoils showed accelerated deposition of leptomeningeal amyloid β (Aβ) with a subset of them developing microinfarcts. In contrast, the CAA mice without hypoperfusion exhibited very few leptomeningeal Aβ depositions and no microinfarcts by 32 weeks of age. Following 12 weeks of hypoperfusion, cerebral blood flow decreased by 26% in CAA mice and by 15% in wild-type mice, suggesting impaired microvascular function due to perivascular Aβ accumulation after hypoperfusion. Our results suggest that cerebral hypoperfusion accelerates CAA, and thus promotes CMIs