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This study investigated PLD1 signaling in synaptic integrity and cognition during aging and in a late-onset AD mouse model, hypothesizing differential effects of PLD1 modulation on synaptic vulnerability. AAV2-mediated gene transfer was employed to overexpress (PLD1 OXP) or attenuate (PLD1 ATT) PLD1 in aged wild-type (WT) and 3xTg-AD mice. To validate these constructs, differentiated PC12 cells were utilized. Within these cells, a model of post-mitotic neurons, PLD1 OXP exhibited a notable reduction in both the average neurite length and the percentage of neurite-bearing cells. This suggests that elevated PLD1 activity exerts a significant influence on neurite outgrowth. Conversely, PLD1 ATT did not inhibit neurite formation, indicating it is not detrimental at the cellular level. These cellular findings paralleled in vivo observations - electrophysiological studies revealed PLD1 OXP impaired long-term potentiation (LTP) and synaptic transmission, particularly in aged WT mice, whereas PLD1 ATT improved synaptic function in 3xTg-AD mice. Behaviorally, PLD1 ATT enhanced spatial working memory and reduced anxiety-like behavior, notably in 3xTg-AD mice. These results highlight that tight PLD1 regulation is vital for maintaining synaptic integrity and cognitive resilience. Thus, PLD1 attenuation may serve as an important complement to immunotherapeutic approaches by strengthening synaptic resilience in neurodysfunctional states, including AD and related dementia (ADRD).<\/jats:p>","DOI":"10.64898\/2025.12.08.692971","type":"posted-content","created":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T15:45:13Z","timestamp":1765467913000},"source":"Crossref","is-referenced-by-count":1,"title":["PLD1-Dependent Regulation of Synaptic Integrity: Implications for Cognitive Resilience and Alzheimer\u2019s Disease Pathogenesis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4427-8605","authenticated-orcid":false,"given":"Sravan Gopalkrishnashetty","family":"Sreenivasmurthy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaneilahi M.","family":"Budhwani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjana","family":"Mohanty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlene E","family":"Villarreal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Poonam","family":"Shah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shyny K","family":"John","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandramouli","family":"Natarajan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karthik","family":"Ramaswamy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle","family":"Sheth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phu Cuong","family":"Phan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose L","family":"Lopez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satkarjeet Kaur","family":"Gill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Currie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klarissa","family":"Garza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agenor","family":"Limon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas A","family":"Green","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2074-4165","authenticated-orcid":false,"given":"Balaji","family":"Krishnan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025121300201173000_2025.12.08.692971v1.1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2021.696476"},{"key":"2025121300201173000_2025.12.08.692971v1.2","doi-asserted-by":"crossref","unstructured":"Barber AJ , del Genio CL , Swain AB , Pizzi EM , Watson SC , Tapiavala VN , Zanazzi GJ & Gaur AB (2023) Age, Sex and Alzheimer\u2019s disease: A longitudinal study of 3xTg-AD mice reveals sex-specific disease trajectories and inflammatory responses mirrored in postmortem brains from Alzheimer\u2019s patients. bioRxiv, 2023.12.23.573209. 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