Abstract
Protein aggregation and amyloid formation are pathogenic events underlying the development of an increasingly large number of human diseases named “proteinopathies”. Abnormal accumulation in affected tissues of amyloid β (Aβ) peptide, islet amyloid polypeptide (IAPP), and the prion protein, to mention a few, are involved in the occurrence of Alzheimer’s (AD), type 2 diabetes mellitus (T2DM) and prion diseases, respectively. Many reports suggest that the toxic properties of amyloid aggregates are correlated with their ability to damage cell membranes. However, the molecular mechanisms causing toxic amyloid/membrane interactions are still far to be completely elucidated. This review aims at describing the mutual relationships linking abnormal protein conformational transition and self-assembly into amyloid aggregates with membrane damage. A cross-correlated analysis of all these closely intertwined factors is thought to provide valuable insights for a comprehensive molecular description of amyloid diseases and, in turn, the design of effective therapies.
Highlights
In the first decade of the last century, Alois Alzheimer described the presence of “amyloid” plaques and neurofibrillary tangles (NFTs) post-mortem in the brain of a woman suffering from cognitive decline and memory loss [1]
Current knowledge concerning the harmful role played by fibril-forming proteins on the structural integrity of plasma membranes suggests that it may be considered a key mechanism at the root of amyloid toxicity
Details concerning the real nature of amyloid/membrane assemblies is of utmost importance due to the clinical implications in the development of new drugs aimed at interfering with membrane disruption by amyloids
Summary
In the first decade of the last century, Alois Alzheimer described the presence of “amyloid” plaques and neurofibrillary tangles (NFTs) post-mortem in the brain of a woman suffering from cognitive decline and memory loss [1] This is the first scientific article which documents a case of a neurological disorder that was later generally identified as Alzheimer’s disease (AD). Protein misfolding and amyloid aggregation are common pathogenic mechanisms of more than 40 progressive diseases, termed protein conformational diseases (PCDs) or proteinopathies, which are the most detrimental in terms of social and health care costs in civilized countries [6] These disorders include AD, type II diabetes mellitus (T2DM) and prion diseases (see Table 1) [7]. We will focus on three different proteinopathies, i.e., AD, T2DM and prion diseases, paying major attention to the role played by amyloid/membrane interaction in the underlying pathogenic events leading to the development of the diseases
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