EVIDENCE THAT TRANSMITTER-CONTAINING DYSTROPHIC NEURITES PRECEDE THOSE CONTAINING PAIRED HELICAL FILAMENTS WITHIN SENILE PLAQUES IN THE ENTORHINAL CORTEX OF NONDEMENTED ELDERLY AND ALZHEIMERS-DISEASE PATIENTS

Within the amygdala of elderly subjects and patients with Alzheimer's disease (AD), we recently found evidence suggesting amyloid beta-prote in (AbetaP) deposition occurs before the appearance of dystrophic neur ites. Moreover, these data suggested dystrophic neurites initially lac k evidence of cytoskeletal pathology although with time and further ma turation, the dystrophic neurites display an altered cytoskeleton as e videnced by their immunoreactivity to Alz-50 and paired-helical filame nts (PHF). These findings are of particular relevance to our understan ding of the sequence of pathologic events in AD and thus it has become important to determine whether these events are unique to the amygdal a or are representative of a more general pattern which can be found t hroughout the brain. Using a battery of antibodies to markers that are characteristic of AD pathology (i.e., AbetaP, PHF, and Alz-50), three peptidergic neurotransmitters (neurotensin, somatostatin, and substan ce P), and one neurotransmitter biosynthetic enzyme (choline acetyltra nsferase), we examined the entorhinal cortex (EC) of three groups of s ubjects (AD, normal elderly, and a group of nondemented elderly with n umerous senile plaques). The EC was studied, in part, because it is we ll recognized as a brain region displaying severe and, most importantl y, early pathologic changes. Like the amygdala, we found evidence that amyloid beta-protein immunoreactive (AbetaP-IR) and thioflavine-S-pos itive senile plaques occur within the EC prior to the appearance of tr ansmitter-, Alz-50-, or PHF-immunoreactive dystrophic neurites. We als o observed transmitter-immunoreactive dystrophic neurites in the absen ce of Alz-50 or PHF-immunolabeled dystrophic neurites and transmitter- and Alz-50-IR dystrophic neurites in the absence of those containing PHF. Collectively, these findings were similar to those seen within th e amygdala and thus reinforced the concept that AbetaP deposition is t he primary event in plaque pathology, and this deposition is subsequen tly followed by the appearance of dystrophic neurites which retain the ir transmitter phenotype yet lack an altered cytoskeleton. With time, these dystrophic neurites develop cytoskeletal alterations and become immunoreactive to Alz-50 and PHF.