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 (A?) 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 A? aggregation (TA?A). To do this, we will use a triple transgenic mouse where three major genes associated with familial Alzheimer?s disease are expressed leading to TA?A. 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 A? 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 TA?A 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 TA?A, 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 TA?A 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.

Public Health Relevance

The focus of this research is on the sleep related function of a brain network that is affected by Tau and amyloid beta deposition in Alzheimer?s disease and the relationship between these functional changes and impaired memory in Alzheimer?s disease. This research is relevant to public health because it will increase knowledge about the role of changes in the functional interactions between the cortex and hippocampus and use current technologies to perform a functional dissection of Tau and amyloid beta clearance in these critical brain circuits, including a noninvasive approach for clearing tau and amyloid beta. The proposal is relevant to NIH?s mission in that it will expand the knowledge base, and establish a new research platform for understanding the mechanism of impaired memory in Alzheimer?s disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Cell Death in Neurodegeneration Study Section (CDIN)
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Mackiewicz, Miroslaw
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Florida State University
United States
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