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

• Published in: Acta pharmacologica Sinica Vol. 38; no. 9; pp. 1205 - 1235
• Main Authors: Chen, Guo-fang, Xu, Ting-hai, Yan, Yan, Zhou, Yu-ren, Jiang, Yi, Melcher, Karsten, Xu, H Eric
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2017; Nature Publishing Group
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - metabolism; Amyloid precursor protein; Animals; Antibodies; Antibodies - chemistry; Antibodies - metabolism; Biomedical and Life Sciences; Biomedicine; Dementia; Dementia disorders; Humans; Immunology; Internal Medicine; Medical Microbiology; microRNA; miRNA; Neurodegenerative diseases; Neuromodulation; Neurotoxicity; Pharmacology/Toxicology; Plaques; Protein Conformation; Proteins; Proteolysis; Review; Secretase; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Tau protein; Vaccine; Vaccines; Vaccines - chemistry; Vaccines - pharmacology; β-Amyloid; β-淀粉样蛋白; 治疗; 淀粉样前体蛋白; 结构生物学; 蛋白酶抑制剂; 阿尔茨海默氏病; 阿尔茨海默病; amyloid beta peptide; neurodegenerative diseases; drug discovery; amyloid precursor protein; Alzheimer's disease
• ISSN: 1671-4083; 1745-7254; 1745-7254
• DOI: 10.1038/aps.2017.28

Amyloid beta peptide （Aβ） is produced through the proteolytic processing of a transmembrane protein, amyloid precursor protein （APP）, by β- and y-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 y-secretase; Aβ-degrading proteases; tau protein inhibitors and vaccines; amyloid dyes and microRNAs.