Genetic Association of <i>CDC2</i> with Cerebrospinal Fluid Tau in Alzheimer’s Disease

Abstract

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 β-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, 626} = 7.0, p = 0.001) and the homozygous CDC2 Ex6 + 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.

Confronting complexity in late‐onset Alzheimer disease: application of two‐stage analysis approach addressing heterogeneity and epistasis

“…CDC2 has been associated with AD and with increased levels of tau in cerebrospinal fluid (Johansson A et al, 2003;Johansson A et al, 2005). However, we were not able to replicate these findings in a previous analysis of our complete dataset (Liang X et al, 2007b).…”

Association Analysis of Genetic Polymorphisms in the CDC2 Gene with Late-Onset Alzheimer Disease

“…The selective accumulation of CDC2 in neurons bearing neurofibrillary tangles indicates that a mitotic posttranslational mechanism might contribute to the paired helical filament-tau formation in AD [24] . Johansson et al [25] reported that an insertion/ deletion polymorphism influences total tau protein levels in the cerebrospinal fluid using analysis of continuous traits.…”

“…Johansson et al [25] sequenced all coding exons, flanking intronic sequences and the promoter region in 10 AD cases and 10 controls and found three polymorphisms [EX6 + 7I/D (rs3212319), rs2456777 and rs2456778], all within 74 bp of each other. We genotyped these three SNPs and three additional SNPs to cover the region.…”

Mitochondrial fragmentation in neurodegeneration

“…In addition, studies have found increased levels of Cdk4 in ischemic brain tissue and mouse models of ALS,89, 90 increased levels of Cdk2 and Cdk4 in postmortem brain samples from AD patients,91 and increased Cdk5 activity in MPTP models of PD 92. Furthermore, genetic studies have linked certain polymorphisms of Cdk1 with increased susceptibility to Alzheimer’s disease 93, 94. As mentioned above, Cdk1 can phosphorylate Drp1, increase its activity and stimulate mitochondrial fragmentation 46.…”