{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T06:12:27Z","timestamp":1788415947751,"version":"build-2803163510"},"reference-count":178,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>The ability of AD treatments targeting classic pathological proteins to achieve meaningful clinical outcomes has been severely limited, shifting attention to the earlier upstream pathways that drive disease progression. Increasing evidence indicates that synaptic mitochondrial dysfunction is an early pathological event that directly contributes to synaptic loss and cognitive decline. This review focuses on how four interrelated pathologies\u2014disrupted energy metabolism, calcium overload, imbalanced mitochondrial fission\/fusion, and defective autophagy\u2014converge to impair synaptic function and plasticity. Emerging therapeutic strategies aimed at protecting and restoring synaptic mitochondrial health, including mitochondria-targeted antioxidants, metabolic modulators, calcium signaling inhibitors, dynamics regulators, and autophagy inducers, are also examined. A central focus of the review is clinical translation: we summarize the preclinical evidence and critically evaluate major obstacles such as the lack of synapse-specific biomarkers, challenges in blood\u2013brain barrier penetration and targeted delivery, and substantial patient heterogeneity. Rather than proposing a fully defined translational framework, we highlight the essential requirements for building one, centered on synaptic mitochondrial bioenergetics and quality control. Specifically, early and accurate biomarkers must be developed, patients should be stratified promptly, and rational combination therapies with complementary mechanisms need to be implemented. This organelle-centered perspective will clarify AD pathogenesis and help guide the development of next-generation neuroprotective therapies.<\/jats:p>","DOI":"10.3389\/fphar.2026.1849218","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T05:14:25Z","timestamp":1788412465000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Synaptic mitochondrial dysfunction and Alzheimer\u2019s disease: from molecular mechanisms to therapeutic strategies"],"prefix":"10.3389","volume":"17","author":[{"given":"Yuxin","family":"Wang","sequence":"first","affiliation":[{"name":"School of Basic Medicine, Heilongjiang University of Chinese Medicine","place":["Harbin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weidong","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Basic Medicine, Heilongjiang University of Chinese Medicine","place":["Harbin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lishuang","family":"Yan","sequence":"additional","affiliation":[{"name":"School of Basic Medicine, Heilongjiang University of Chinese Medicine","place":["Harbin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Basic Medicine, Heilongjiang University of Chinese Medicine","place":["Harbin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quan","family":"Li","sequence":"additional","affiliation":[{"name":"School of Basic Medicine, Heilongjiang University of Chinese Medicine","place":["Harbin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyan","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Basic Medicine, Heilongjiang University of Chinese Medicine","place":["Harbin, China"]},{"name":"Key Laboratory of Basic Theory Research on Traditional Chinese Medicine","place":["Harbin, Heilongjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"C465","DOI":"10.1152\/ajpcell.00502.2020","article-title":"Molecular nature and physiological role of the mitochondrial calcium uniporter channel","volume":"320","author":"Alevriadou","year":"2021","journal-title":"Am. 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