数据日期 2026-10-29 · 生成时间 2026-10-29 06:03
研究问题
Dementia represents a major unmet therapeutic need.
方法
This was a narrative review rather than a systematic review; therefore, no protocol-driven screening, duplicate-independent study selection, or formal meta-analytic risk-of-bias procedure was undertaken [18,19].；Neuropeptides are retained in this review only as an indirect comparator group.；Evidence-level descriptors used in the candidate matrices are operational rather than subjective. “Direct AChE/PAS evidence” requires compound-specific biochemical, binding, biophysical, structural, or mutational evidence of interaction; “secondary mechanism demonstrated” requires an independently measured disease-relevant mechanism in the same candidate; “clinical evidence” requires human intervention data with defined endpoints; and “not established” means that no qualifying evidence was identified in the narrative searches described in Section 2, not that absence of evidence has been proven by a systematic review.；Therapeutic Perspectives: A Practical Translational Framework for Multifunctional AChE Modulators The therapeutic perspective developed in this review is centred on a staged…
核心结论
In a seminal experimental study, AChE was shown to accelerate the assembly of amyloid-β (Aβ) peptides into fibrils, whereas this effect was reduced by ligands interacting with the peripheral anionic site (PAS) [10].；The World Health Organization reported that 57 million people were living with dementia worldwide in 2021 and that nearly 10 million new cases occur each year; Alzheimer’s disease accounts for an estimated 60–70% of dementia cases.；Searches were structured around PubMed/MEDLINE, Scopus, Web of Science, and Embase using combinations of the following concepts: (acetylcholinesterase OR AChE) AND (peripheral anionic site OR PAS) AND (peptide* OR peptidomimetic* OR peptide analogue*) AND (Alzheimer* OR dementia OR cholinergic OR amyloid-β OR tau OR neuroprotect*). ‖ 结论：Overall, the field should be regarded as an emerging, experimentally testable design space rather than a clinically established therapeutic class; progress will depend on rigorous separation of direct and indirect mechanisms, orthogonal target-engagement studies, quantitative CNS pharmacology, and evidence-gated translational development.
局限
BBB-shuttle approaches, receptor-mediated transcytosis, cell-penetrating or carrier-assisted systems, lipid-based nanoparticles, and intranasal administration may improve CNS exposure, but none should be considered sufficient on the basis of delivery alone [35,92,93,94,95,96,111].；Future studies should quantify exposure of the intact active species in the relevant brain compartment and determine whether chemical modification or formulation preserves AChE/PAS interaction and the intended secondary pharmacology [13,41,91,100,107].；Future work should therefore prioritize experimentally testable sequence–structure–activity relationships rather than expanding the number of phenotypic activities…
对本项目的价值
★★★☆☆ 脑老化是最大未满足需求，也是终点最难量化的领域；biomarker 与认知读数选择最敏感。命中核心 线粒体；最大样本量约 313；设计 系统综述。
全文来源
PMC JATS 全文（正文 93,386 字符，已过标题/DOI 逐字归属校验）
原文题录
- 英文标题：Peptides and Peptide Analogues Targeting Acetylcholinesterase-Associated Mechanisms in Alzheimer's Disease and Dementias: Evidence Gaps, Design Strategies, and Translational Perspectives.
- 期刊与标识：Int J Mol Sci · PMID 42941873 · DOI 10.3390/ijms27209094**
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