1Department of Pharmacy and Yonsei Institute of Pharmaceutical Science, Yonsei University, Incheon 21983, Republic of Korea 2Department of Pharmacy, Yonsei Institute of Pharmaceutical Science, and Department of Integrative Biotechnology, College of Pharmacy, Yonsei University, Incheon 21983, Republic of Korea
*Corresponding Author : YoungSoo Kim
Abstract
ConspectusA century ago, German neurologist Alois Alzheimer documented the first case of Alzheimer's disease (AD), illuminating cognitive impairments associated with the presence of abnormal protein clusters, including amyloid plaques and tau tangles, within the brain. In a typical physiological state, the equilibrium of amyloid-β (Aβ) levels is maintained, but aging can precipitate disruptions in the homeostasis of Aβ due to its overproduction, impaired clearance, and other factors, ultimately leading to its accumulation. Although the link between Aβ aggregates and neurodegeneration has long made Aβ a promising target for AD, decades without successful drug development targeting Aβ have generated skepticism regarding the efficacy of this strategy for AD therapy. However, recent approvals of anti-Aβ antibody drugs by the FDA, including aducanumab (Aduhelm), lecanemab (Leqembi), and donanemab (Kisunla), have prompted a re-evaluation of this perspective. These therapies have demonstrated efficacy in reducing brain Aβ levels, thereby decelerating disease progression and reaffirming Aβ as a key target. Despite advancements, immunotherapies are accompanied by considerable disadvantages, including adverse effects, high costs, and cumbersome administration. To address these limitations, our research has focused on developing small molecules that can mitigate the challenges of antibody treatments while offering practical and accessible options. We identified 4-(2-hydroxyethyl)-1-piperazine propanesulfonic acid (EPPS) as a promising compound that significantly reduces aggregated Aβ in the brain and enhances behavior in AD rodent models. Following administration, EPPS penetrates the blood-brain barrier (BBB) and binds to toxic Aβ aggregates, subsequently breaking them down into nontoxic monomers. This leads to two significant outcomes: a reduction of Aβ aggregates in the brain and a subsequent increase in Aβ monomers in blood. The monomeric Aβ, unlike its aggregated form, can now traverse the BBB and enter the bloodstream. This mechanism provides an innovative approach to AD treatment and diagnosis. By detaching cerebral Aβ aggregates, EPPS facilitates Aβ clearance and addresses a key pathological feature of AD. Concurrently, the increase in blood Aβ levels offers a potential biomarker for monitoring treatment efficacy and disease progression, thereby revolutionizing both AD treatment and diagnosis. Investigating the detailed mode of action of drug candidates requires structural information about a target protein. Unfortunately, the unstable and heterogeneous nature of Aβ aggregates, which form larger clusters, complicates the identification of these structures. Therefore, we developed new tools for screening small molecules by immobilizing monomeric Aβ and its fragments on plates. This allows us not only to identify novel compounds that target Aβ but also to elucidate their mechanisms of action, enabling the development of Aβ-targeting therapeutic avenues in AD. We believe that our work on chemical-driven amyloid clearance through small molecules represents an advance in AD research, offering chemical diversity and straightforward, economical development processes. In clinical practice, we anticipate that these findings will contribute to the development of patient-friendly therapeutic and diagnostic interventions, including self-administered and orally available options, thereby enhancing disease management and overall quality of life for individuals with AD. Furthermore, this research extends beyond AD, potentially offering insights into other neurodegenerative diseases characterized by protein aggregation.
본 논문은 연세대학교 약학대학 화학생물학실험실에서 수행된 알츠하이머병 연구의 성과 중, 뇌 내 아밀로이드베타(Aβ) 단백질 응집체 제거에 초점을 맞춰, 진단 및 치료법 개발을 위한 새로운 가능성을 제시한 연구들만 엮어 설명한 논문입니다. 본 리뷰에서, 기존의 항체 치료법(예: 아두카누맙, 레카네맙)의 효과와 함께, 고가의 비용, 부작용, 정맥주사 투여 등의 임상적 한계를 간략히 논의하고, 이러한 한계를 극복하기 위한 대안으로, 우리 연구실에서 발견한 소분자인 EPPS를 이용한 아밀로이드 제거 전략을 제시합니다.