NEW INSIGHTS INTO THE NEUROPATHOLOGY AND CELL BIOLOGY OF ALZHEIMERS-DISEASE

Several Lines of evidence, including newly discovered genetic mutation s, suggest that beta-amyloid (A beta) is directly involved in the neur opathology observed in familial and sporadic forms of Alzheimer's dise ase (AD). Rather than exerting its neurotoxicity directly, results fro m our Laboratory suggest that fibrillar A beta (fA beta) activates mic roglia and astrocytes upon injection into the rat brain. The microglia and astrocytes, in turn, form a functional barrier between A beta and surrounding neurons. An increase in inducible nitric oxide synthase ( iNOS) immunoreactivity is observed in activated microglia and astrocyt es, and specific subpopulations of neurons are lost in fA beta injecti on areas versus controls. These data, coupled with recent discoveries of the A beta association with the receptor for advanced glycation end products (RAGE) and the class A scavenger receptors (SR), support the hypothesized sized role of inflammatory mechanisms in AD neurotoxicit y.