REELIN INCREASES PLAQUE-ASSOCIATED MICROGLIAL ACCUMULATION AND AMYLOID-Β PHAGOCYTOSIS IN ALZHEIMER’S DISEASE PRECLINICAL MODELS

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and cognitive decline. Its pathological hallmarks include amyloid-beta (Aβ) plaque deposition, neurofibrillary tangles, and neuroinflammation. Reelin, an extracellular matrix glycoprotein, plays a pivotal role in neural development and adult plasticity. Previous work, including ours, has demonstrated its multifaceted impact on AD, including limiting amyloid aggregation, reducing phosphorylated Tau pathology and amyloid production, and preserving cognitive function. Microglia, the brain's immune cells, are key responders to brain damage in AD. They bind Aβ oligomers through various receptors, leading to phenotypic activation, proliferation, enhanced phagocytosis, and cytokine production. Given that microglia express Reelin receptors, we investigated whether Reelin modulates microglial activation states and enhances Aβ phagocytosis. Using immunohistochemistry coupled with confocal imaging, we combined the J20 AD mouse model with Reelin gain-of-function (J20OE) or loss-of-function (J20KO) models to analyze microglial homeostatic markers (Tmem119, P2RY12) and activation-associated markers (TREM2, IFITM3, CD68, …). Our results indicate that Reelin overexpression: 1) increases microglial accumulation around dense-cored amyloid plaques, potentially limiting plaque-associated neurotoxicity; 2) enhances microglial-mediated Aβ phagocytosis, concomitant with a reduced amyloid burden; and 3) promotes local microglial proliferation in plaque-associated niches. Furthermore, single-cell RNA sequencing (scRNA-seq) of purified microglia revealed distinct microglial subpopulations that are selectively modulated by Reelin levels. Together, these findings identify Reelin as a previously unrecognized regulator of microglial phenotype and function, enhancing microglial Aβ clearance and revealing a novel mechanism contributing to amyloid reduction in AD.