Apolipoprotein E (APOE) genotype strongly impacts several major pathological features of Alzheimer’s disease (AD), including extracellular β-amyloid (Aβ) deposits, intracellular tau tangle formation, and microglial dysfunction. The metabolism and signaling of ApoE in the brain are controlled by members of the lipoprotein receptor superfamily, and genetic manipulation of ApoE receptors has been shown to significantly impact AD pathology. Hence, the pathways modulating ApoE receptors in the brain represent promising targets for the therapeutic intervention in AD. Previously, we have identified the inducible degrader of the LDLR (IDOL), an E3 ubiquitin ligase, is a major post-translational regulator of three ApoE receptors: low-density lipoprotein receptor (LDLR), very low-density lipoprotein receptor (VLDLR), and ApoE Receptor 2 (ApoER2). Each of these ApoE receptor plays key role in modulating ApoE actions and impacting AD pathogenesis in the brain. We showed that both genetic deletion and therapeutic reduction of IDOL increases brain ApoE receptors levels, decreases Aβ levels, and improves cognitive functions in mouse models of Aβ amyloidosis. Our recent mechanistic research revealed IDOL knockdown markedly increases microglial phagocytosis of fibrillar Aβ in vivo, and the subpopulation of disease-associated microglia (DAM), a phagocytic microglia population associated with Aβ plaques. Our research also suggests that LDLR, an IDOL substrate, plays an important role in facilitating metabolic reprogramming of microglia during phagocytosis likely by mediating the uptake of ApoE lipoproteins. Furthermore, IDOL regulates the expression of ApoER2, a receptor that is enriched in the postsynaptic membrane of excitatory synapses. ApoER2-mediated signaling is known to increase glutamatergic neurotransmission and antagonize Aβ-induced suppression of synaptic functions. We showed that manipulation of IDOL expression in neuron is sufficient to modulate synaptic transmission. Based on these results, our goals of this proposal are to delineate molecular mechanisms by which IDOL-ApoE receptor pathway modulates ApoE actions and impacts Aβ pathology. Aim 1 is to define the role of IDOL in facilitating microglial response to Aβ and impacting the progression of Aβ pathology. Aim 2 is to elucidate the mechanisms of how IDOL-LDLR axis facilitates metabolic reprogramming and ApoE signaling in microglia. Aim 3 is to delineate the role of neuronal IDOL in enhancing ApoER2-mediated signaling and protecting against Aβ-induced synaptic dysfunction and cognitive deficit.