LYSOSOMAL ABNORMALITIES IN DEGENERATING NEURONS LINK NEURONAL COMPROMISE TO SENILE PLAQUE DEVELOPMENT IN ALZHEIMER-DISEASE

Antibodies to the lysosomal hydrolases, cathepsins B and D and beta-he xosaminidase A, revealed alterations of the endosomal-lysosomal system in neurons of the Alzheimer disease brain, which preceded evident deg enerative changes and became marked as atrophy, neurofibrillary pathol ogy, or chromatolysis developed. At the earliest stages of cell atroph y, hydrolase-positive lysosomes accumulated at the basal pole and then massively throughout the perikarya and proximal dendrites of affected pyramidal neurons in Alzheimer prefrontal cortex and hippocampus, far exceeding the changes of normal aging. Secondary lysosomes as well as tertiary residual bodies (lysosomes/lipofuscin) increased implying st imulated, autophagocytosis and lysosomal system activation. Less affec ted brain regions, such as the thalamus, displayed similar though less extensive alterations. Certain thalamic neurons exhibited a distincti ve lysosome-related abnormality characterized by the presence of cell surface blebs of varying size and number filled with intense hydrolase immunoreactivity. At more advanced stages of degeneration in still in tact neurons, hydrolase-positive lipofuscin, particularly in the form of abnormally large aggregates, nearly filled the cytoplasm. Similar l ipofuscin aggregates were observed in abundance in the extracellular s pace following cell lysis and were usually associated with deposits of the beta-amyloid protein. Degenerating neurons and their processes we re the major source of these aggregates within senile plaques which co ntained high concentrations of acid hydrolases. We have shown in previ ous studies that these lysosomal hydrolases in plaques are enzymatical ly-active. The persistence of lysosomal structures in the brain parenc hyma after neurons have degenerated is a striking and potentially diag nostic feature of Alzheimer disease which has not been observed, to ou r knowledge, in other degenerative diseases. The lysosomal response in degenerating Alzheimer neurons represents a probable link between an early activation of the lysosomal system in at-risk, normal-appearing neurons and the end-stage contribution of lysosomes to senile plaque f ormation and emphasizes a slowly progressive disturbance of the lysoso mal system throughout the development of Alzheimer disease.