Gas6:Axl regulation of microglia immune function and Alzheimer's pathogenesis

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The distinct pathology of AD includes extracellular deposits of amyloid-b (Ab), intracellular accumulation of hyperphosphorylated tau protein, and wide-spread neuroinflammation. Despite genetic evidence that Ab drives Alzheimer’s disease (AD) pathology, efforts to intervene with immunotherapies and secretase inhibitors have essentially all failed, indicating that the amyloid hypothesis is not sufficient to explain the full pathological course. Instead, accumulating evidence reveals an intertwining of these three pathologies, which together drive the synaptic loss and neural disconnection that lead to dementia. Our work and that of others supports a model in which neuroinflammation links amyloid and tau pathology, and can directly contribute to synaptic loss, vascular dysfunction, and oxidative damage. Microglia are essential drivers of neuroinflammation that show dramatic phenotypic changes in neurodegenerative diseases and express disease-associated microglial (DAM) genes, including some recognized as risk factors for AD (e.g. TREM2 and ApoE). Thus, targeting microglial activation represents an important potential therapeutic approach to AD and other neurodegenerative conditions. One identified DAM is Axl, a receptor tyrosine kinase that is upregulated in AD, particularly in microglia associated with amyloid plaques. Binding of Axl’s ligand, growth-arrest specific protein 6 (Gas6) has multimodal effects that include both initiation of phagocytosis and suppression of inflammation. Despite the association of Axl- expressing microglia with amyloid deposits, Axl’s role in Ab phagocytosis is not known, nor is it known whether microglial Axl signaling modifies the inflammatory environment and other AD pathologies such as tau. Based on our preliminary studies, we hypothesize that activation of Axl signaling with Gas6 can be used to increase Ab phagocytosis and suppress inflammation, providing a beneficial effect on other disease-associated endpoints such as tau phosphorylation and cognitive dysfunction. This idea, and the corollary hypothesis that loss of Axl signaling increases AD pathology, will be tested in APP/PS1 and P301S tau mice as well as in primary microglial cultures using genetic and pharmacologic approaches. Our proposed experiments will provide fundamental information about the role of Gas6:Axl signaling in microglia, and help determine whether modulating Axl activity provides a tractable therapeutic approach for AD using preclinical models.