The Pursuit of the Inside of the Amyloid Hypothesis-Is C99 a Promising Therapeutic Target for Alzheimer's Disease?

卷:12

Review

关键词: BETA-SECRETASE CLEAVAGE;    C-TERMINAL FRAGMENT;    A-BETA;    PRECURSOR PROTEIN;    GAMMA-SECRETASE;    MOUSE MODEL;    DOWN-SYNDROME;    INTRACELLULAR ACCUMULATION;    NEUROFIBRILLARY TANGLES;    LYSOSOMAL DYSFUNCTION;   

DOI  :  10.3390/cells12030454

来源: SCIE

【 摘 要 】

Aducanumab, co-developed by Eisai (Japan) and Biogen (U.S.), has received Food and Drug Administration approval for treating Alzheimer's disease (AD). In addition, its successor antibody, lecanemab, has been approved. These antibodies target the aggregated form of the small peptide, amyloid-beta (A beta), which accumulates in the patient brain. The amyloid hypothesisbased therapy that places the aggregation and toxicity of A beta at the center of the etiology is about to be realized. However, the effects of immunotherapy are still limited, suggesting the need to reconsider this hypothesis. A beta is produced from a type-I transmembrane protein, A beta precursor protein (APP). One of the APP metabolites, the 99-amino acids C-terminal fragment (C99, also called beta CTF), is a direct precursor of A beta and accumulates in the AD patient's brain to demonstrate toxicity independent of A beta. Conventional drug discovery strategies have focused on A beta toxicity on the outsideof the neuron, but C99 accumulation might explain the toxicity on the insideof the neuron, which was overlooked in the hypothesis. Furthermore, the common region of C99 and A beta is a promising target for multifunctional AD drugs. This review aimed to outline the nature, metabolism, and impact of C99 on AD pathogenesis and discuss whether it could be a therapeutic target complementing the amyloid hypothesis.