PLAQUE BIOGENESIS IN BRAIN AGING AND ALZHEIMERS-DISEASE - II - PROGRESSIVE TRANSFORMATION AND DEVELOPMENTAL SEQUENCE OF DYSTROPHIC NEURITES

Plaque-associated dystrophic neurites are a common pathological featur e in the brains of patients with Alzheimer's disease (AD). In the pres ent study, we investigated the relative abundance and progressive tran sformation of the amyloid precursor protein (APP), neurofilament (NF) and paired helical filament (PHF) tau-positive dystrophic neurites, wi thin plaques in non-demented controls versus plaque-associated dystrop hic neurites in mild or severe AD using double and triple immunolabeli ng. We also determined the argentophilia of the various sub-population s of dystrophic neurites. In aged non-demented brain, approximately ha lf of the APP-positive plaques contained NF-immunopositive dystrophic neurites; rarely were PPTF/tau-positive dystrophic neurites detectable . In contrast, in the AD brain, three-fourths of the APP-positive plaq ues contained NF-positive dystrophic neurites and half contained PHF/t au neurites. We also observed focal patches of hyper-phosphorylated NF and/or PHF/tau within APP-immunopositive dystrophic neurites, which a ppeared similar to retrograde degeneration, whereas we never observed focal accumulations of APP within NF- or PHF/tau-positive fibers. We h ypothesize that plaque-associated dystrophic neurites within plaques d evelop in a particular sequence: APP-positive dystrophic neurites appe ar first and are non-argentophilic. This is followed by the appearance of NF-positive dystrophic neurites, where a subset of NF-positive dys trophic neurites are lightly argentophilic. Over time, PHF/tau-positiv e dystrophic neurites develop and are strongly argentophilic. These da ta suggest that dystrophic neurites can develop retrogradely from foca l plaque damage to induce somatic and dendritic degeneration and poten tially contribute to neurofibrillary tangle formation.