AMYLOID IN ALZHEIMERS-DISEASE AND PRION-RELATED ENCEPHALOPATHIES - STUDIES WITH SYNTHETIC PEPTIDES

Deposition of amyloid-beta protein (beta A) in brain parenchyma and ve ssel walls is a major pathological feature of Alzheimer's disease (AD) . In prion-related encephalopathies (PRE), too, an altered form of pri on protein (PrPsc) forms amyloid fibrils and accumulates in the brain. In both conditions the amyloid deposition is accompanied by nerve cel l loss, whose pathogenesis and molecular basis are not understood. Neu ropathological, genetic and biochemical studies indicate a central rol e of beta A in the AD pathogenesis. Synthetic peptides homologous to b eta A and its fragments contribute to investigate the mechanisms of be ta A deposit formation acid the role played by beta A in AD pathogenes is. The physicochemical studies on the beta-sheet conformation and sel f-aggregation properties of beta A peptides indicate the conditions an d the factors influencing the formation of beta A deposits. The neurot oxic activity of beta A and its fragments support the causal relations hip between beta A deposits and the neuropathological events in AD. Nu merous studies were performed to clarify the mechanism of neuronal dea th induced by exposure to beta A peptides. A similar approach has been used to investigate the role of PrPsc in PRE; in these diseases, the association between accumulation of PrPsc and neuropathology is eviden t and numerous data indicate that PrPsc itself might be the infectious agent responsible for disease transmission. Thus, PrP peptides were u sed to investigate the pathogenic role of PrPsc in PRE and the conform ational change responsible for the conversion PrPc to PrPsc that makes the molecule apparently infectious. In particular, we synthesized a p eptide homologous to residues 106-126, an integral part of all abnorma l PrP isoforms that accumulate in the brain of subjects' PRE. This pep tide is fibrillogenic, has secondary structure largely composed of bet a-sheet and proteinase-resistant properties, is neurotoxic and induces astrogliosis. In this review, we summarize and compare the data obtai ned with beta A and PrP peptides and analyze the significance in terms of amyloidogenic proteins and neurodegeneration. Copyright (C) 1996 E lsevier Science Ltd.