{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:57:15Z","timestamp":1785412635329,"version":"3.56.0"},"posted":{"date-parts":[[2025,11,11]]},"group-title":"Neuroscience","reference-count":87,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T00:00:00Z","timestamp":1762819200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["R01AG067325"],"award-info":[{"award-number":["R01AG067325"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,11,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Recent advancements in Alzheimer\u2019s disease (AD) therapeutics have validated the use of amyloid beta (A\u03b2)-clearing antibodies, which reduce A\u03b2 pathology but leave other disease hallmarks largely unaddressed. Since AD involves multiple pathological processes, additional strategies are needed to target complementary mechanisms. One such target is autophagy, a lysosomal mediated degradation pathway essential for cellular homeostasis that removes toxic protein aggregates and damaged organelles. This process is implicated in AD, as impaired lysosomal function promotes A\u03b2 and tau accumulation. Our laboratory recently identified a novel natural mitophagy-inducing compound (MIC) that may serve as a therapeutic intervention for AD.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We evaluated the effects of MIC in aged 3xTgAD mice, a transgenic model displaying both A\u03b2 and tau pathology. Mice received either standard diet or diet containing MIC beginning at age 4 months until 20 months on alternating weeks. Age-matched non-transgenic (NonTg) controls were included under standard and MIC-supplemented diets to assess compound effects during normal aging. Neuropathological changes were assessed using immunohistochemistry (IHC) for A\u03b2, phosphorylated tau (pTau), and microglial reactivity. Cognitive performance was evaluated using the Morris Water Maze (MWM) to assess spatial learning and memory and the Y-maze to measure working memory.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>At 20 months of age, our neuropathological assessment showed that 3xTgAD mice fed an MIC-supplemented diet had a significant reduction in pTau accumulation and microglial reactivity, although A\u03b2 burden remained unchanged. At 15 months, MIC diet also improved spatial learning and memory in aged NonTg controls but not in 3xTgAD mice. However, in younger 8-month-old 3xTgAD mice, MIC restored working memory performance to NonTg levels, indicating an age-dependent therapeutic response.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>MIC emerges as a potential modulator of tau pathology and neuroinflammation. As a naturally derived compound, MIC offers potential for combination therapy with FDA-approved A\u03b2-clearing antibodies, enabling a multimodal approach to AD treatment that addresses amyloid, tau, and microglia-related pathology.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.11.09.687389","type":"posted-content","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T15:40:19Z","timestamp":1762875619000},"source":"Crossref","is-referenced-by-count":0,"title":["A Compound Enhancing Lysosomal Function Reduces Tau Pathology, Microglial Reactivity and Rescues Working Memory in 3xTg AD Mice"],"prefix":"10.64898","author":[{"given":"Zachary","family":"Mayeri","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgia","family":"Woods","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anand","family":"Rane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Kifle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manish","family":"Chamoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shikha","family":"Shukla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaska C.","family":"Walton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie K.","family":"Andersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025111407200474000_2025.11.09.687389v2.1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(16)00062-4"},{"issue":"1","key":"2025111407200474000_2025.11.09.687389v2.2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jalz.2011.10.007","article-title":"National Institute on Aging\u2013Alzheimer\u2019s Association guidelines for the neuropathologic assessment of Alzheimer\u2019s disease","volume":"8","year":"2012","journal-title":"Alzheimer\u2019s & Dementia"},{"key":"2025111407200474000_2025.11.09.687389v2.3","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a006189"},{"key":"2025111407200474000_2025.11.09.687389v2.4","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(94)90458-8"},{"key":"2025111407200474000_2025.11.09.687389v2.5","doi-asserted-by":"publisher","DOI":"10.1126\/science.1566067"},{"key":"2025111407200474000_2025.11.09.687389v2.6","doi-asserted-by":"publisher","DOI":"10.1038\/ng1095-219"},{"key":"2025111407200474000_2025.11.09.687389v2.7","doi-asserted-by":"publisher","DOI":"10.1126\/science.1072994"},{"key":"2025111407200474000_2025.11.09.687389v2.8","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaw0930"},{"key":"2025111407200474000_2025.11.09.687389v2.9","doi-asserted-by":"publisher","DOI":"10.1038\/nature02621"},{"key":"2025111407200474000_2025.11.09.687389v2.10","unstructured":"Biogen , LECANEMAB CONFIRMATORY PHASE 3 CLARITY AD STUDY MET PRIMARY ENDPOINT, SHOWING HIGHLY STATISTICALLY SIGNIFICANT REDUCTION OF CLINICAL DECLINE IN LARGE GLOBAL CLINICAL STUDY OF 1,795 PARTICIPANTS WITH EARLY ALZHEIMER\u2019S DISEASE. 2022."},{"key":"2025111407200474000_2025.11.09.687389v2.11","doi-asserted-by":"publisher","DOI":"10.1056\/NEJ-Moa2212948"},{"key":"2025111407200474000_2025.11.09.687389v2.12","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.13239"},{"key":"2025111407200474000_2025.11.09.687389v2.13","doi-asserted-by":"crossref","unstructured":"Tampi, R.R. , B.P. 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