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Neurogenetics

Apolipoprotein E (APOE, gene; apoE, protein) exists in the general population as three commen genetic variations, called APOE2, E3, and E4. APOE4 is a suceptibility gene, or risk factor, for Alzheimer's disease (AD). The APOE4 allele frequency is highly significantly increased in affected individuals in both familial and sporadic late-onset AD. The inheritance of APOE4 is associated with an increased risk of disease expression and a younger age of onset in a dose-dependent manner. The effect of the more uncommon allele, APOE2, is to decrease the risk and increase the age of onset compared to the most common APOE3 allele. Thus, the effect of inheriting specific APOE alleles is associated with regulating the age of disease expression of AD. ApoE antibodies stain neurons in autopsy brains from elderly controls and AD patients. In AD patients, many apoE immunoreactive neurons also contain immunoreactive neurofibrillary tangles. Furthermore, in situ hybridization studies have localized apoE within neuronal cytplasm. We have demonstrated that apoE3 binds nonphosphorylated tau in vitro to form an SDS-stable complex and that there is little to no binding of apoE4 to tau. Neither isoform binds to phosphorylated tau. ApoE3 binding occurs in the microtubule binding repeat domains of the tau molecule. Studies with synthetic repeat domain peptides show that the binding of apoE3 is not dependent on the formation of disulfide bonds. Evidence for a model to explain the rate of disease expression as a function of APOE genotype, where apoE3 and apoE2 play a protective role by sequestering free tau and facilitating microtubule stabilization, is supported by neuronal degeneration studies of APOE knock-out mice.


Headings
APOE genotype, Alzheimer's disease (AD)

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