Amyloid in Alzheimer's disease and prion-related encephalopathies: Studies with synthetic peptides

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Deposition of amyloid-β protein (βA) in brain parenchyma and vessel walls is a major pathological feature of Alzheimer's disease (AD). In prion-related encephalopathies (PRE), too, an altered form of prion protein (PrPsc) forms amyloid fibrils and accumulates in the brain. In both conditions the amyloid deposition is accompanied by nerve cell loss, whose pathogenesis and molecular basis are not understood. Neuropathological, genetic and biochemical studies indicate a central role of βA in the AD pathogenesis. Synthetic peptides homologous to βA and its fragments contribute to investigate the mechanisms of βA deposit formation and the role played by βA in AD pathogenesis. The physicochemical studies on the β-sheet conformation and self-aggregation properties of βA peptides indicate the conditions and the factors influencing the formation of βA deposits. The neurotoxic activity of βA and its fragments support the causal relationship between βA deposits and the neuropathological events in AD. Numerous studies were performed to clarify the mechanism of neuronal death induced by exposure to βA 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 evident and numerous data indicate that PrPsc itself might be the infectious agent responsible for disease transmission. Thus, PrP peptides were used to investigate the pathogenic role of PrPsc in PRE and the conformational change responsible for the conversion PrPc to PrPsc that makes the molecule apparently infectious. In particular, we synthesized a peptide homologous to residues 100-l26, an integral part of all abnormal PrP isoforms that accumulate in the brain of subjects' PRE. This peptide is fibrillogenic, has secondary structure largely composed of β-sheet and proteinase-resistant properties, is neurotoxic and induces astrogliosis. In this review, we summarize and compare the data obtained with βA and PrP peptides and analyze the significance in terms of amyloidogenic proteins and neurodegeneration.

Original languageEnglish
Pages (from-to)287-315
Number of pages29
JournalProgress in Neurobiology
Issue number4
Publication statusPublished - Jul 1996

ASJC Scopus subject areas

  • Neuroscience(all)

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