The role of ciliary melanin-concentrating hormone receptors in Alzheimer's disease

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Project Abstract Primary cilia are cellular organelles with sensory functions. Ciliopathy is defined as a disease associated with abnormal cilia function or structure. Ciliopathies are associated with expanding spectrum of kidney, liver, and cardiovascular disorders. However, it is yet to be investigated whether or not Alzheimer’s disease (AD) is associated with cilia function and structure. In this Administrative Supplement proposal, we combine expertise from two laboratories of the neighboring institutions. This multi-PI proposal includes Dr. Surya Nauli (Chapman University), whose laboratory has strong records in interrogating primary cilia functions, and Dr. Amal Alachkar (the University of California, Irvine), whose research group has strong expertise in neurological degeneration of AD. The overall goal of this proposal is to examine the alterations of cilia structure and functions in early- and late-stage AD mouse brains. It is known that melanin concentrating hormone receptor (MCHR1) is localized in cilia of neuronal cells within the frontal cortex and hippocampus. In Aim 1, we will investigate if the deletion of MCHR1-expressing cilia exacerbates cognitive deficits in 5xFAD mouse model of AD. We will use both cilia and AD mouse models to study behavioral and memory changes in these mice. In Aim 2, we examine if selective pharmacological targeting of ciliary MCHR1 improve cognitive deficits in AD. We will apply nanoparticle- targeting, which is part of the parental grant to evaluate if ciliary MCHR1-targeted therapy improves the behavioral deficits in 5xFAD-AD mice. The outcomes of these limited studies offer new knowledge if MCHR1- expressed cilia (Aim 1) and ciliary MCHR1 (Aim 2) are involved in behavioral deficits in AD mice.