Protein Interactome of Amyloid-β as a Therapeutic Target

Abstract

The amyloid concept of Alzheimer’s disease (AD) assumes the β-amyloid peptide (Aβ) as the main pathogenic factor, which injures neural and other brain cells, causing their malfunction and death. Although Aβ has been documented to exert its cytotoxic effect in a solitary manner, there is much evidence to claim that its toxicity can be modulated by other proteins. The list of such Aβ co-factors or interactors includes tau, APOE, transthyretin, and others. These molecules interact with the peptide and affect the ability of Aβ to form oligomers or aggregates, modulating its toxicity. Thus, the list of potential substances able to reduce the harmful effects of the peptide should include ones that can prevent the pathogenic interactions by specifically binding Aβ and/or its partners. In the present review, we discuss the data on Aβ-based complexes in AD pathogenesis and on the compounds directly targeting Aβ or the destructors of its complexes with other polypeptides.

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“…Therefore, tau protein accumulation in MPS suggests impaired autophagy [92], which can also negatively impact neurological symptoms, as shown in several other diseases, such as Alzheimer's, Parkinson's, and Huntington's diseases [93][94][95]. β-amyloid accumulation would also have a negative effect on the brain, as shown in previous studies [96].…”

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“…Other pathological conditions coexist with Aβ in 98% of early-onset AD (EOAD) and in 100% of late-onset AD (LOAD) ( 3 ). Co-pathologies include Cerebral Amyloid Angiopathy (CAA), Lewy Body disease (alpha-synucleinopathies), Limbic-predominant age-related TPD-43 (LATE), Hippocampal Sclerosis (HIS), Argyrophilic Grain Disease (AGD), vascular disease, Aging-related tau astrogliopathy (ARTAG), and Argyrophilic Thorny Astrocytes in clusters (ATAC) ( 3 , 14 ).…”

“…This might be a relevant bias when searching for the imaging biomarkers of AD and when testing eligibility to therapeutics that are specific for the neuronal deposition of Aβ. The presence of intravascular amyloid may lead to the overestimation of results from brain PET, thus categorizing variants that are mixed by a neuropathological point of view as “pure” Aβ-related AD forms ( 14 ). This “dilution effect” may reduce the effect of anti-Aβ monoclonal antibodies.…”

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“…The interaction of Aβ species with various proteins in the AD brain is an area of increasing importance, and studies of the Aβ interactome have the potential to provide novel therapeutic targets [ 75 ]. One of the most studied protein interactions in AD is that of Aβ and APOE4 [ 76 , 77 ].…”

“…The interaction of Aβ species with various proteins in the AD brain is an area of increasing importance, and studies of the Aβ interactome have the potential to provide novel therapeutic targets [75]. One of the most studied protein interactions in AD is that APOE4/4 patients represent a distinct, high-risk Alzheimer's population APOE is a lipoprotein that transports cholesterol and Aβ in the brain and plasma.…”