Amyloid beta: structure, biology and structure-based therapeutic development

Abstract

Amyloid beta peptide (Aβ) is produced through the proteolytic processing of a transmembrane protein, amyloid precursor protein (APP), by β-and γ-secretases. Aβ accumulation in the brain is proposed to be an early toxic event in the pathogenesis of Alzheimer's disease, which is the most common form of dementia associated with plaques and tangles in the brain. Currently, it is unclear what the physiological and pathological forms of Aβ are and by what mechanism Aβ causes dementia. Moreover, there are no efficient drugs to stop or reverse the progression of Alzheimer's disease. In this paper, we review the structures, biological functions, and neurotoxicity role of Aβ. We also discuss the potential receptors that interact with Aβ and mediate Aβ intake, clearance, and metabolism. Additionally, we summarize the therapeutic developments and recent advances of different strategies for treating Alzheimer's disease. Finally, we will report on the progress in searching for novel, potentially effective agents as well as selected promising strategies for the treatment of Alzheimer's disease. These prospects include agents acting on Aβ, its receptors and tau protein, such as small molecules, vaccines and antibodies against Aβ; inhibitors or modulators of β-and γ-secretase; Aβ-degrading proteases; tau protein inhibitors and vaccines; amyloid dyes and microRNAs.

Microglial inflammation and phagocytosis in Alzheimer's disease: Potential therapeutic targets

“…Neuronal loss can start years before symptoms develop and initially localises to the hippocampus and entorhinal cortex in early stages of disease. The most widely accepted explanation for AD, known as the “amyloid hypothesis,” proposes that misfolding and aggregation of the peptide β‐amyloid (Aβ) causes a linear cascade of pathology that results in both extracellular amyloid plaques and intracellular deposition of misfolded Tau protein that forms neurofibrillary tangles (Chen et al, ; C. C. Tan, Zhang, Tan, & Yu, ). Since the amyloid hypothesis was first proposed, the linearity of this mechanism has been brought into question, with suggestions that amyloid and Tau pathologies may occur concurrently or even independently (De Strooper & Karran, ).…”

Alzheimer's Aβ1‐40 peptide degradation by thermolysin: evidence of inhibition by a C‐terminal Aβ product

“…The peptides derive from the amyloid precursor protein (APP), which is present in neurons, oligodendrocytes, and neuronal synapses, and has attributed functions such as regulation of synaptic transmission and metal transport [2]. Structural models of the complexes of TLN with several Ab fragments show that, despite the numerous possible cleavage sites of the Ab sequence, the C-terminal product of Ala30-Ile31 cleavage does not dissociate, thus inhibiting the enzyme.…”

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The interaction of the amyloid-b peptide (Ab) with thermolysin (TLN) was investigated by X-ray crystallography. Ab is generated when APP is cleaved in an amyloidogenic way, by a two-step b-secretase/c-secretase cleavage [2].Advances aim at modulating the elimination of Ab, either in a monomeric, oligomeric, or fibrillary form, are underway. The high similarity between the TLN structural motif and neprilysin (NEP), the most extensively studied peptidase associated with Ab clearance, suggests that NEP should be more efficient against Ab polymorphs where Ala30-Ile31 is inaccessible, which is in agreement with studies in living mice that point to the limited role of NEP in degrading soluble Ab and its higher ability to degrade insoluble and/or oligomeric Ab forms, producing only the Ab 10-37 intermediate.

Keywords: b-turn-b conformation; amyloid-b peptide cleavage; amyloid-b peptide/thermolysin; thermolysin inhibition; X-ray crystallography

The "amyloid hypothesis" has been the cornerstone of Alzheimer's disease (AD) research for the past decades, placing the amyloid-b peptide (Ab) at the heart of the pathology [1].

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“…The peptides derive from the amyloid precursor protein (APP), which is present in neurons, oligodendrocytes, and neuronal synapses, and has attributed functions such as regulation of synaptic transmission and metal transport [2]. Ab peptides are usually 36-43 residues in length, constituting the main component of amyloid aggregates found in the brains of Alzheimer's patients, with Ab 1-40 and Ab 1-42 (subscript numbers indicate residue number) being the two most common and studied forms.…”

“…The peptides derive from the amyloid precursor protein (APP), which is present in neurons, oligodendrocytes, and neuronal synapses, and has attributed functions such as regulation of synaptic transmission and metal transport [2]. Ab is generated when APP is cleaved in an amyloidogenic way, by a two-step b-secretase/c-secretase cleavage [2].Advances aim at modulating the elimination of Ab, either in a monomeric, oligomeric, or fibrillary form, are underway. However, such action may be counterproductive, because several physiological roles are being linked to Ab, such as blood clotting, neuronal cell survival, and even gene expression regulation [3][4][5].…”