EVIDENCE THAT TRANSMITTER-CONTAINING DYSTROPHIC NEURITES PRECEDE PAIRED HELICAL FILAMENT AND ALZ-50 FORMATION WITHIN SENILE PLAQUES IN THE AMYGDALA OF NONDEMENTED ELDERLY AND PATIENTS WITH ALZHEIMERS-DISEASE

Immunocytochemical techniques were employed to examine the temporal or dering whereby amyloid beta-protein (AbetaP) and neuronal elements col lectively come together to form senile plaques in Alzheimer's disease (AD). Specifically, we addressed three questions: (1) whether AbetaP d eposition precedes or follows neuritic changes; (2) whether paired hel ical filament (PHF) formation is an early or late event in the genesis of the dystrophic neurites which participate in plaque formation; and (3) whether the density of senile plaques displays any relationship w ith the prevalence of PHF or Alz-50 containing neurons. To address the se questions we studied the amygdala from a group of patients with AD, a group of nondemented age-matched individuals exhibiting a sufficien t number of senile plaques to be classified by neuropathological crite ria as AD, and a group of age-matched controls without AD pathology. A myloid-bearing plaques were demonstrated by AbetaP immunolabeling and thioflavine-S staining. Neuritic changes in the form of dystrophic neu rites were observed with the aid of antibodies against PHF, Alz-50, as well as antibodies against several neuropeptides (i.e., substance P, somatostatin, and neurotensin) and the acetylcholine biosynthetic enzy me, choline acetyltransferase. By using a graded range of pathologic c hanges both within and across the patient population to provide us wit h a means of evaluating plaque deposition from its earliest to most ad vanced stages of development, we observed in patients and/or regions o f the amygdala displaying a mild degree of pathologic change AbetaP de position in the absence of any neuritic changes. With increasing densi ty of AbetaP, however, we began to observe dystrophic neurites within plaques. In regions of relatively few plaques, the dystrophic neurites were immunolabeled only with antibodies against the various neurotran smitters and they lacked evidence of cytoskeletal pathology (i.e., Alz -50 or PHF). Only as the density of AbetaP increased further within a region, were dystrophic neurites observed that exhibited Alz-50 or PHF . In no instance did we observe a relationship between the density of AbetaP deposition and the density of Alz-50 or PHF-immunoreactive neur ons. Collectively, our data suggest that the deposition of AbetaP is a n early pathologic event in senile plaque formation. Thereafter, swoll en neurites can be seen in the vicinity of AbetaP. This early neuritic response, which can first be visualized by immunolabeling for one or another transmitter substance, is followed by alterations in the cytos keleton as recognized initially by antibodies to Alz-50 and subsequent ly by the presence of PHF. (C) 1993 Wiley-Liss, Inc.