Altered Diversity of Astrocyte sub-types and Signaling Capabilities in Alzheimer's Disease

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Project Summary/Abstract Alzheimer’s Disease (AD) has been identified as one of the highest priority neurobiological diseases in need of research advancement, inflicting progressive cognitive impairment on patients, and excessive burden on caregivers and families. Due to the lack of effective preventative or reparative treatments for AD, it is imperative to identify cellular or circuit factors contributing to the impairments in learning and memory. It has long been observed that glial cells are noticeably altered, morphologically and molecularly, under conditions of neurodegeneration and inflammation, including in AD. Astrocytes in particular have critical roles in synaptic function, integration of circuit responses, and network homeostasis. It is yet unclear how activity-dependent dynamics of intracellular signaling in these cells are altered under disease conditions. Due to the anatomical importance of the dentate gyrus, the heterogeneous signaling characteristics of hippocampal astrocytes, and the involvement of inflammatory processes in AD, we postulate that: dentate gyrus astrocytes maintain diverse signaling capabilities in response to distinct neuronal circuit activation, and that these signals are differentially vulnerable to AD pathology. Using selective circuit stimulation and membrane-tagged calcium imaging in two distinct populations of astrocytes of the dentate gyrus, we will investigate the capabilities and susceptibilities of astrocyte responses to neurotransmission and neuromodulation. Adaptation of calcium datasets to new computational analysis toolsets specifically designed for the unique characteristics of astrocyte signaling will be used to categorize and profile capabilities of hilar and molecular layer astrocytes in control animals and in the 5xFAD animal model of AD. Furthermore, we shall attempt to identify astrocyte sub-populations and alterations in astrocyte diversity within the dentate gyrus, using single-cell sequencing, cluster analysis, and examination of differentially expressed genes and pathways. In this way, we will define the susceptible sub-populations of astrocytes in AD, and reveal alterations in gene expressions in these critically important cells as they undergo pathology-related modifications. Results from this study will greatly inform on the potential of targeting specific subsets of astrocytes in development of AD therapies, and will provide a database of transcript levels by which to measure effectiveness of potential interventions.