Based on molecular structures: Amyloid-β generation, clearance, toxicity and therapeutic strategies

Abstract

Amyloid-β (Aβ) has long been considered as one of the most important pathogenic factors in Alzheimer’s disease (AD), but the specific pathogenic mechanism of Aβ is still not completely understood. In recent years, the development of structural biology technology has led to new understandings about Aβ molecular structures, Aβ generation and clearance from the brain and peripheral tissues, and its pathological toxicity. The purpose of the review is to discuss Aβ metabolism and toxicity, and the therapeutic strategy of AD based on the latest progress in molecular structures of Aβ. The Aβ structure at the atomic level has been analyzed, which provides a new and refined perspective to comprehend the role of Aβ in AD and to formulate therapeutic strategies of AD.

Polyphenols’ Impact on Selected Biomarkers of Brain Aging in Healthy Middle-Aged and Elderly Subjects: A Review of Clinical Trials

“…Aβ fibers or oligomers can promote the formation of new Aβ oligomers, generating greater toxic effects, and they can disrupt endosome vesicles and interfere with the transport of brain-derived neurotrophic factors. Additionally, the internalization of oligomers can trigger intracellular systemic damage, increase endoplasmic reticulum stress, mediate calcium imbalance and hence, can lead to the activation of apoptotic caspase 3 [68]. Some of the Aβ peptides (including dimers, trimers, hexamers, and 12-meres) can be imported into the mitochondria, where they bind to the inner membrane and interfere with complex I of the respiratory chain [69].…”

Oxidative Stress Occurs Prior to Amyloid Aβ Plaque Formation and Tau Phosphorylation in Alzheimer’s Disease: Role of Glutathione and Metal Ions

“…However, escalated production or decreased clearance of these Aβ peptides or both result in the accumulation of inflammatory SPs that impair cell signaling pathways and result in subsequent synaptic degeneration, neuronal loss, and decline in cognitive functions . Oligomeric Aβ is found to be highly neurotoxic, and primarily the Aβ 40 and Aβ 42 isoforms can aggregate and form Aβ plaques in the brain . Aβ plaques, however, are also observed in the autopsied brains of healthy individuals with no history of cognitive impairment before death. , Thus, the presence of Aβ plaque deposition does not necessarily correlate with abnormal clinical findings. ,, …”

Chaperone Activity and Protective Effect against Aβ-Induced Cytotoxicity of Artocarpus camansi Blanco and Amaranthus dubius Mart. ex Thell Seed Protein Extracts

“…Alzheimer’s disease (AD) is considered the most common type of dementia and is listed as the sixth-leading cause of death in the United States [ 1 ]. Currently, 6.7 million Americans aged 65 and older are living with AD and it is expected that global AD patients will triple by 2050 [ 2 , 3 ]. AD is characterized by the formation of amyloid-beta (Aβ) peptide aggregates on senile plaques (SP) and neurofibrillary tangles formed by tau deposition [ 3 , 4 , 5 ].…”

“…Currently, 6.7 million Americans aged 65 and older are living with AD and it is expected that global AD patients will triple by 2050 [ 2 , 3 ]. AD is characterized by the formation of amyloid-beta (Aβ) peptide aggregates on senile plaques (SP) and neurofibrillary tangles formed by tau deposition [ 3 , 4 , 5 ]. Amyloid-beta (Aβ) peptide is a proteolytic fragment of 39–43 amino acid residues derived from the amyloid precursor protein (APP).…”

“…SP are mainly composed of the 40- (Aβ 1–40 ) and 42-residue-long peptides (Aβ 1–42 ), where Aβ 1–40 is the most abundant and Aβ 1–42 the more aggregation-prone [ 6 ]. The aggregation of Aβ 1–40 and Aβ 1–42 into insoluble fibrils is considered the major pathological hallmark of AD [ 3 , 7 , 8 ]. It has proven to be toxic, leading to memory loss and cognitive decline over time.…”