Hypothesis: Microtubule Instability and Paired Helical Filament Formation in the Alzheimer Disease Brain Are Related to Apolipoprotein E Genotype

摘要: A genetic classification of Alzheimer disease(s) (AD) is presented. We describe a potential metabolic process in individuals who inherit apolipoprotein E-epsilon 4 (APOE4, gene; apoE4, protein) alleles, leading to increased risk and earlier age onset late-onset disease. Apolipoprotein 3 (apoE3) binds tau protein, possibly slowing the initial rate phosphorylation self-assembly into paired helical filaments (PHFs); apoE4 does not bind tau. Tau promotes microtubule assembly stabilizes microtubules; hyperphosphorylated bind, thereby destabilizing microtubules. Hyperphosphorylated may self-assemble PHFs. Over time bias toward destabilization microtubules formation neurofibrillary tangles occur APOE4 shorter functional neuronal life span. This hypothesis focuses attention on two important aspects AD research design: (1) Although inheritance associated with decreased onset, directly cause Our data point absence an function apoE3 or apoE2 do these alleles as genetically relevant factor. has implications for design experiments directed understanding metabolism. (2) Should this be proven confirmed, targets pharmaceutical therapy designed mimic become realistic preventive strategy.