Neurodegenerative reprograming of microglia in Alzheimer’s disease

Advanced Science Research Center, New York NY

Investigators

Abstract

ABSTRACT Genetic studies implicate microglia—the brain's primary innate immune cells—as major determinants for the risk of Alzheimer's Disease (AD). In murine AD models, microglia can assume phenotypes with protective or neurodegenerative functions, such as driving aberrant synapse loss. This proposal aims to elucidate molecular mechanisms that identify and give rise to functionally neurodegenerative microglia—a critical knowledge gap in the field. The results may inform future therapeutic avenues in the treatment of AD via the elimination of these microglia. Ultrastructural studies in humans and mice discovered a subset of “dark” microglia, characterized by signs of cellular stress, prominent chromatin compaction, and frequent contact with synaptic elements in conditions of pathological synapse loss. This grant is based on the premise of these studies, which attributed a neurodegenerative role to microglia with cellular stress. We recently discovered that a conserved stress signaling pathway, the integrated stress response (ISR), is activated in dark microglia. Using two novel mouse models that allow us to turn on or off ISR cell-autonomously in microglia, we showed that ISR is sufficient to generate the dark microglia phenotype in the absence of external stimuli. In murine amyloid and tau models of AD, inducing ISR in microglia worsened their neurodegenerative impact while inhibiting ISR ameliorated them. ISR can result from exposure to diverse genetic (e.g., APOE4 allele) and non-genetic (e.g., aging) risk factors for AD. Therefore, the driving hypothesis is that ISR—triggered by risk factors—serves as an upstream event that epigenetically reprograms microglia, exacerbating their stressed phenotype upon exposure to amyloid pathology and worsening neurodegeneration. To address this hypothesis, we will first determine the mechanisms of ISR-induced chromatin remodeling. Second, we will test whether ISR exacerbates the stressed phenotypes of microglia in amyloidosis models. Third, we will test if ISR worsens the neurodegenerative impact of microglia in amyloidosis and tau models. The proposed framework provides conceptual innovation to the field of AD by focusing on interlinked cellular stress and epigenetic mechanisms in the neurodegenerative reprogramming of the brain's resident immune cells. Mechanistic deconstruction of this process is possible due to our technically innovative approaches that combine novel mouse models with advanced molecular techniques and by leveraging biotechnological tools and expertise available at the state-of-the-art core facilities at CUNY Advanced Science Research Center and other New York institutes, as well as our productive collaboration with co-PI Dr. Marie-Ève Tremblay.