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bioRxiv · 10.1101/2025.11.09.687389

An Autophagy-Inducing Compound Reduces Tau Pathology, Microglia Reactivity, and Rescues Working Memory in 3xTg AD Mice

Mayeri, Z.·Woods, G.·Rane, A.·Kifle, A.·Chamoli, M.·Shukla, S.·Walton, C. C.·Andersen, J. K.
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Abstract

BackgroundRecent advancements in Alzheimers disease (AD) therapeutics have validated the use of amyloid beta (A{beta})-clearing antibodies, which reduce A{beta} 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{beta} and tau accumulation. Our laboratory recently identified a novel natural mitophagy-inducing compound (MIC) that may serve as a therapeutic intervention for AD. MethodsWe evaluated the effects of MIC in aged 3xTgAD mice, a transgenic model displaying both A{beta} 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{beta}, 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. ResultsAt 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{beta} 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. ConclusionMIC 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{beta}-clearing antibodies, enabling a multimodal approach to AD treatment that addresses amyloid, tau, and microglia-related pathology.

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Mayeri, Z., Woods, G., Rane, A., Kifle, A., Chamoli, M., Shukla, S., Walton, C. C., Andersen, J. K.. 2025-11-12. An Autophagy-Inducing Compound Reduces Tau Pathology, Microglia Reactivity, and Rescues Working Memory in 3xTg AD Mice. https://doi.org/10.1101/2025.11.09.687389

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