Targeting the orexin pathway to treat sleep disorders and improve glymphatic clearance in Alzheimer’s disease

PROJECT SUMMARY/ABSTRACT FOR FUNDED GRANT Note, this is a redundant copy required by our submission system, the abstract is also included within the 5 page Research strategy as requested in the application instructions. Alzheimer’s disease is devastating for individuals and society. Impaired learning and memory,

particularly in the context of spatial navigation, is one of its early and major symptoms. Similarly, rodents recapitulating aspects of Alzheimer’s disease also exhibit early impairments in spatial navigation. A preponderance of evidence suggests abnormal cortical-hippocampal communication in humans with Alzheimer’s disease. Hippocampal-cortical interactions during sleep

are thought to be critical for consolidation of newly acquired memories. However, no studies have assessed these brain dynamics during sleep in rodents modeling Tau and amyloid beta (Aβ) aggregation aspects of Alzheimer’s disease. Thus, the proposed research will explore the functionality of brain dynamics during sleep in the hippocampal-PC network in animal models of

Tau and Aβ aggregation (TAβA). To do this, we will use a triple transgenic mouse where three major genes associated with familial Alzheimer’s disease are expressed leading to TAβA. This mouse model mimics plaque and tangle pathological hallmarks of the disease, with a distribution pattern similar to human patients, including synaptic changes in the limbic system. In addition, all

findings will be confirmed in a transgenic rat with Aβ accumulation, plaque formation, tau accumulation, cell loss, and spatial memory impairments. Specifically, we will: 1) assess the relationship between spatial learning and memory, as well as brain dynamics during sleep, both within and across the hippocampus and cortex; 2) use a novel targeted optogenetic approach

to functionally dissect the relative contributions of TAβA in the hippocampus to impaired hippocampal-cortical coupling during sleep and impaired spatial learning. 3) test the efficacy of a non-invasive visual stimulation approach, known for clearing cortical TAβA, to relieve impaired hippocampal-cortical coupling during sleep and impaired spatial learning. This project

will provide insight into the normal function of a circuit that is dysfunctional in Alzheimer’s disease and allow us to probe dysfunction in this circuit that emerges in very early stages of disease progression in rodents modeling TAβA aspects of Alzheimer’s disease. This research will allow us to begin understanding changes in this network which may underlie the emergence of cognitive

impairments observed in Alzheimer’s disease and begin testing the efficacy of a non-invasive treatment for reversing the functional brain abnormalities and impaired cognition.