Abstract
Amyloid fibrils are physiologically insoluble biophysically specific β-sheet rich structures formed by the aggregation of misfolded proteins. In vivo tissue amyloid formation is responsible for more than 30 different disease states in humans and other mammals. One of these, Alzheimer's disease (AD), is the most common form of human dementia for which there is currently no definitive treatment. Amyloid fibril formation by the amyloid β-peptide (Aβ) is considered to be an underlying cause of AD, and strategies designed to reduce Aβ production and/or its toxic effects are being extensively investigated in both laboratory and clinical settings. Transthyretin (TTR) and proteins containing a BRICHOS domain are etiologically associated with specific amyloid diseases in the CNS and other organs. Nonetheless, it has been observed that TTR and BRICHOS structures are efficient inhibitors of Aβ fibril formation and toxicity in vitro and in vivo, raising the possibility that some amyloidogenic proteins, or their precursors, possess properties that may be harnessed for combating AD and other amyloidoses. Herein, we review properties of TTR and the BRICHOS domain and discuss how their abilities to interfere with amyloid formation may be employed in the development of novel treatments for AD.
Highlights
The amyloidoses are a set of human diseases in which the precursors, synthesized as soluble proteins, aggregate and become insoluble under physiologic conditions
The sequence of AβPP cleavage followed by aggregation of amyloid β-peptide (Aβ) fragments is causal in the rare autosomal dominant forms of Alzheimer’s disease (AD) and is likely to participate in the pathogenesis of the sporadic disease, but may not be the sole etiology in the latter
We will discuss the available information describing the biologic and biophysical findings that are apparently involved in the prevention of one form of amyloid, i.e., that formed by the Aβ protein seen in the plaques in human AD, by BRICHOS and TTR, molecules that are direct precursors of other distinct forms of human amyloidosis and what this may mean in the universe of protein-protein interactions in complex organisms
Summary
The amyloidoses are a set of human diseases (and their animal models) in which the precursors, synthesized as soluble proteins, aggregate and become insoluble under physiologic conditions. Current thinking, based on genetic, biochemical and in vivo observations, favors the notion that cleavage fragments of the normal single pass transmembrane molecule AβPP, i.e., Aβ1–38–43, which are aggregation prone, form oligomers, which can be shown to be cytotoxic in tissue culture and synaptotoxic in hippocampal slices (Selkoe and Hardy, 2016). The sequence of AβPP cleavage followed by aggregation of Aβ fragments is causal in the rare autosomal dominant forms of AD and is likely to participate in the pathogenesis of the sporadic disease, but may not be the sole etiology in the latter In both forms there appears to be a multiplicity of contemporaneous or downstream events involving other cell types (microglia, astrocytes) and proteins, Tau, which contribute to the development of the characteristic dementia. We will discuss the available information describing the biologic and biophysical findings that are apparently involved in the prevention of one form of amyloid, i.e., that formed by the Aβ protein seen in the plaques in human AD, by BRICHOS and TTR, molecules that are direct precursors of other distinct forms of human amyloidosis and what this may mean in the universe of protein-protein interactions in complex organisms
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