{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T23:47:33Z","timestamp":1789429653064,"version":"build-2803163510"},"reference-count":216,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:00:00Z","timestamp":1781136000000},"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. Synaptic Neurosci."],"abstract":"<jats:p>\n                    Synaptic failure is one of the earliest and most significant contributors to the cognitive decline in Alzheimer\u2019s disease (AD), preceding extensive neuronal loss. Although amyloid beta (A\u03b2) plaques and neurofibrillary tangles (NFTs) of tau protein characterize the disease, memory impairment primarily results from the gradual deterioration of synaptic communications. This decline is caused by a complex interaction among mitochondrial energy deficits, cytoskeletal instability, disrupted exosomal signaling, and immune-mediated synaptic pruning. Mitochondrial dysfunction, particularly affecting complexes I and IV, leads to reduced ATP production, faulty mitophagy and disrupted calcium (Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ) homeostasis, placing the synapse under constant metabolic stress. Elevated reactive oxygen species (ROS) further activate stress pathways, including p38 MAPK and JNK, contributing to synaptic protein damage and impaired long-term potentiation (LTP). Furthermore, tau hyperphosphorylation destabilizes the neuronal cytoskeleton, weakening dendritic spine integrity and synaptic connectivity. At the same time, A\u03b2 alters the cargo carried by exosomes, facilitating the spread of pathogenic A\u03b2 and tau species between the neurons and modulating microglial activation and complement-mediated synaptic pruning. Additionally, emerging studies highlight the role of NETosis in exacerbating neuroinflammation and compromising the blood-brain barrier (BBB) integrity, thereby increasing synaptic damage. In contrast, phytochemicals such as resveratrol, ginkgolide B, curcumin, ferulic acid, epigallocatechin gallate (EGCG), and quercetin exert neuroprotection by restoring redox balance, altering exosomal communications, stabilizing cytoskeletal signaling, and reducing neuroinflammation. Moreover, delivery techniques such as nanoparticles and engineered exosomes enhance BBB permeability and enable targeted synaptic intervention. Overall, this review summarizes current mechanistic findings and highlights the potential of phytochemicals as multitarget therapeutic agents for synaptic repair and functional recovery in AD.\n                  <\/jats:p>","DOI":"10.3389\/fnsyn.2026.1835778","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T05:48:00Z","timestamp":1781156880000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Mechanistic insights into the synaptic damage-repair and regeneration processes in neurodegenerative Alzheimer\u2019s disease: phytochemicals as neuroprotective agents"],"prefix":"10.3389","volume":"18","author":[{"given":"Bharti","family":"Yadav","sequence":"first","affiliation":[{"name":"Department of Zoology, School of Basic Sciences, Central University of Punjab","place":["Bathinda, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prabhakar","family":"Gangwar","sequence":"additional","affiliation":[{"name":"Department of Zoology, School of Basic Sciences, Central University of Punjab","place":["Bathinda, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirti","family":"Kumari","sequence":"additional","affiliation":[{"name":"Department of Zoology, School of Basic Sciences, Central University of Punjab","place":["Bathinda, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anuradha","family":"Yadav","sequence":"additional","affiliation":[{"name":"Department of Zoology, School of Basic Sciences, Central University of Punjab","place":["Bathinda, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rashmi","family":"Rao","sequence":"additional","affiliation":[{"name":"Department of Zoology, School of Basic Sciences, Central University of Punjab","place":["Bathinda, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keshav","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Zoology, School of Basic Sciences, Central University of Punjab","place":["Bathinda, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harkomal","family":"Verma","sequence":"additional","affiliation":[{"name":"Department of Zoology, School of Basic Sciences, Central University of Punjab","place":["Bathinda, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monisha","family":"Dhiman","sequence":"additional","affiliation":[{"name":"Department of Microbiology, School of Basic Sciences, Central University of Punjab","place":["Bathinda, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anil Kumar","family":"Mantha","sequence":"additional","affiliation":[{"name":"Department of Zoology, School of Basic Sciences, Central University of Punjab","place":["Bathinda, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1007\/s10048-025-00821-y","article-title":"Multi-target approach to Alzheimer\u2019s disease prevention and treatment: antioxidant, anti-inflammatory, and amyloid-modulating mechanisms.","volume":"26","author":"Abbas","year":"2025","journal-title":"Neurogenetics"},{"key":"B2","doi-asserted-by":"publisher","first-page":"117739281986641","DOI":"10.1177\/1177392819866412","article-title":"Bacopa monnieri, a neuroprotective lead in alzheimer disease: a review on its properties, mechanisms of action, and preclinical and clinical studies.","volume":"13","author":"Abdul Manap","year":"2019","journal-title":"Drug Target Insights"},{"key":"B3","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1254\/jphs.11r01cr","article-title":"Pharmacological aspects of the acetylcholinesterase inhibitor galantamine.","volume":"116","author":"Ago","year":"2011","journal-title":"J. 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