MHCI and synapse loss in Alzheimer's disease models

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SUMMARY Despite decades of research, the cause of Alzheimer’s disease (AD) remains incompletely understood, current treatments provide only minimal symptom relief, and there are no known cures. AD has consistently been associated with aberrations in both synaptic and immune signaling pathways. However, a key gap in knowledge is a lack of insight into how these two pathways cross communicate to initiate and sustain AD- associated deficits. Work from our lab indicates that the classical major histocompatibility complex I (MHCI) immune molecules are attractive candidates for linking immune signaling to synaptic deficits in AD. MHCI molecules are expressed in the brain, specifically in neurons and at synapses, where they limit excitatory synapse density and function. Recently, we found that surface MHCI (sMHCI) is upregulated in response to amyloid-β (Aβ) and loss of MHCI prevents Aβ-induced synapse loss, thereby implicating this immune signaling in AD pathology for the first time. MHCI may cause this synaptic degeneration through a novel interaction we recently discovered between MHCI and neuroligin-1 (NL1), a synaptic adhesion molecule that modulates synapse formation and plasticity. NL1 is downregulated by Aβ and this decrease is necessary for Aβ-induced decreases in synapse density. NL1 has also been shown to be misregulated in humans with AD. Together, our results suggest the hypothesis that MHCI acts through NL1 to cause synapse loss in AD and induce hippocampal-dependent behavioral deficits. The central goal of this proposal is to determine the role for MHCI signaling, and its interaction with the synaptic modulator NL1, in AD-associated synaptic and behavioral phenotypes. To address this hypothesis, our lab has assembled tools from years of research related to both MHCI and NL1, an innovative and novel long-term live imaging assay to study synapse dynamics, and the expertise of new personnel in AD research and behavioral assays. We propose to explore three aims: (i) determine if changes in sMHCI are required for Aβ-induced synapse loss in vitro, (ii) determine if sMHCI requires NL1 signaling to cause Aβ-induced synapse loss in vitro, and (iii) determine if sMHCI is required for AD-associated in vivo synaptic and behavioral phenotypes. If successful, this proposal will provide valuable insight into the potential of MHCI as a therapeutic target for mitigating the synaptic and cognitive phenotypes associated with AD.