Chief, Division of Neurology in the Department of MedicineDepartments / Divisions
Durham, NC 27710
Alzheimer's disease, dementia, and other memory disorders
Apolipoprotein (apoE) has been recently implicated in the pathogenesis of Alzheimer's disease (A.D.). One of the apoE alleles, e4, behaves as an autosomal co-dominant trait in the majority of late-onset and sporadic A.D.. The aopE4 gene dose is a major risk-factor susceptibility gene for A.D. with homozygosity for this allele virtually sufficient to cause disease by age 80, and with 50% of homozygous patients developing disease by age 68. Incontrast, the e2 and e3 alleles decrease the probability of disease, and increase the age of onset. Thus the inherited apoE allele determines in part, the risk of developing A.D., and determines the rate of disease progression. Interactions of apoE protein with other molecules is therefore critical in the disease process, with isoforms-specific interactions of apoE determining th eprobability, and rate, of disease expression.
The three common protein isoforms of apoE; E2, E3, E4, differ from each other by one amino acid, which determines their profoundly differing interactions with other proteins. In vitro, apoE4 binds BA peptide faster, and with a different pH dependence, than does apoE3. This isoform-specific difference observed in vitro correlates with the greater BA peptide amyloid burden deposited in situ in homozygous e4 A.D. patients, compared with homozygous e3 A.D. patients. Paired-helical filaments of the neurofibrillary tangle are composed of tau protein. ApoE3 avidly binds tau in vitro, forming a complex not disociated by boiling in SDS. In contrast, apoE4 does not form such a complex. Isoform-specific interactions of apoE with tau could alter tau function or metabolism.
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