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Investigation of microRNA-155 and Apolipoprotein E influence on microglial activation in mouse models of Alzheimers disease

Microglia, the resident immune cells of the brain, play a critical role in brain homeostasis and neurological disease progression. In neurodegenerative diseases, microglia acquire a neurodegenerative phenotype (MGnD), the function of which is poorly understood. MicroRNA-155 (miR-155), a multifunctional microRNA enriched in cells of the immune system, and Apolipoprotein E (APOE), a lipoprotein which is significantly associated with Alzheimer’s disease (AD) risk, critically regulate MGnD. However, the role of these molecules in AD pathogenesis remains unclear. Here, we report that microglial deletion of miR-155 induces an early MGnD response activation state via interferon-ɣ (IFNɣ) signaling in mice. This phenotypic transition increases plaque-associated Apoe, enhances amyloid plaque compaction, reduces neuritic dystrophy and attenuates plaque-associated synaptic degradation, resulting in improved cognition. These findings provide a novel mechanism detailing the phenotypic switch from homeostatic microglia to MGnD, and highlight the beneficial role of IFNɣ responsive MGnD in restricting neurodegenerative pathology and preserving cognitive function in a mouse model of AD. In addition, we demonstrate that Apoe deficient microglia induce an MGnD signature comparable to controls, but enhance MGnD physiological phenotypes including enhanced cognitive behavioral performance and reduced plaque associated neuritic dystrophy. Furthermore, we highlight a potential mechanism by which Apolipoprotein C-1 may attenuate synaptic ß-amyloid accumulation in a mouse model of AD. These findings may serve as the basis novel immunomodulatory therapies targeting microglial miR-155 and APOE to treat AD.

Identiferoai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/47439
Date03 November 2023
CreatorsHerron, Shawn
ContributorsIkezu, Tsuneya
Source SetsBoston University
Languageen_US
Detected LanguageEnglish
TypeThesis/Dissertation

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