ESSENTIAL INVOLVEMENT OF OLIGODENDROGLIAS IN THE PATHOGENESIS OF SPORADIC ALZHEIMER’S DISEASE

Abstract

Sporadic Alzheimer's disease (SAD) is the biggest target of drug development, although its pathological process still has been elusive. It must be promoted (or protected) by genetic factors, however, the research has long been dominated by a single direct causality called the amyloid b (Ab) hypothesis, rejecting alternative ones. We investigated roles of oligodendrocyte (OL) lineage cells in the pathogenesis of SAD by establishing a method to purify and culture adult OL progenitor cells (aOPCs) from the rat hippocampus and by investigating postmortem human brains. We found novel aOPCs expressing plexin-B3 as Ab secreting cells. A small population of plexin-B3+ aOPCs was persistently cultured in fibroblast growth factor 2 (FGF2) and FGF2 withdrawal increased plexin-B3+ but decreased NG2+ aOPCs, with cored plaque-like morphological changes and increased Ab1–42 secretion greater than that of cultured fetal neurons. They express massive amounts of APP, the components of gamma-secretase, and the receptors of apolipoprotein E. In vivo, plexin-B3+ aOPCs distributed throughout the adult brain and spreading depolarization, a common mechanism of cortical injuries, induced unique delayed cortical gliosis of plexin-B3+ aOPCs whose distribution resembles to that of cored senile plaques. In human AD brains, cortical senile plaques were mostly immunostained with plexin-B3 antibodies. These findings suggest that plexin-B3+ aOPCs play essential roles in the pathogenesis of SAD as Ab secreting cells. Fine control of a SAD-type demyelination in the aged cortex would be a novel, promising and unexplored therapeutic target for SAD.