The Pursuit of the “Inside” of the Amyloid Hypothesis—Is C99 a Promising Therapeutic Target for Alzheimer’s Disease?

Nobumasa Takasugi, Masato Komai, Nanaka Kaneshiro, Atsuya Ikeda, Yuji Kamikubo, Takashi Uehara

研究成果査読

抄録

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-β (Aβ), which accumulates in the patient brain. The “amyloid hypothesis” based therapy that places the aggregation and toxicity of Aβ 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. Aβ is produced from a type-I transmembrane protein, Aβ precursor protein (APP). One of the APP metabolites, the 99-amino acids C-terminal fragment (C99, also called βCTF), is a direct precursor of Aβ and accumulates in the AD patient’s brain to demonstrate toxicity independent of Aβ. Conventional drug discovery strategies have focused on Aβ toxicity on the “outside” of the neuron, but C99 accumulation might explain the toxicity on the “inside” of the neuron, which was overlooked in the hypothesis. Furthermore, the common region of C99 and Aβ 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.

本文言語English
論文番号454
ジャーナルCells
12
3
DOI
出版ステータスPublished - 2月 2023

ASJC Scopus subject areas

  • 生化学、遺伝学、分子生物学(全般)

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