Endosomal recycling reconciles the Alzheimer's disease paradox

Abstract

A hub-and-spoke model with endosomal recycling as the hub can reconcile the pathogenic contribution of amyloid precursor protein to Alzheimer's disease.

FIGURE. A proposed ‘hub & spoke’ model for Alzheimer’s disease pathogenesis

Causal genes in early-onset Alzheimer’s disease affect the intracellular processing of the amyloid-precursor protein, while putative causal genes in late-onset disease affect intracellular trafficking. Both classes of genes converge by causing defects in endosomal recycling, a pathogenic event that occurs independent of amyloid. Endosomal recycling defects cause enlarged endosomes, a ‘traffic jam’ phenotype that is a hallmark cytopathology of the disease. Endosomal recycling defects can, through parallel pathways, trigger all four of the disease’s histopathological hallmarks: extracellular and intracellular amyloid pathology, tau pathology, synaptic pathology, and microglia pathology. Like the spokes of a wheel, the downstream pathologies might interconnect, but according to the model they represent the disease’s smoke, not its fire.