Tuesday, April 23, 2024
4/23/2024
By 2050 it is estimated that there will be 13.8 million individuals in the US with Alzheimer's disease (AD), at a cost of over $1.2 trillion per yr, if no disease-modifying therapy is developed. The relative contributions of the AD defining pathological markers, amyloid and hyperphosphorylated tau, to cognitive dysfunction remains controversial, but studies in both AD patients and transgenic mouse models of AD, have shown that amyloid is necessary but not sufficient for the development of cognitive loss which is the key clinical target of AD. There is a growing consensus that it is the response of glial cells in the brain to amyloid that is relevant to neuronal damage and thus cognitive impairment. The capacity of these cells to phagocytose and clear amyloid and perhaps other deleterious material in the brain may have a substantial influence on the initiation and progression of the disease. The complement cascade, a powerful effector mechanism of the immune system that is directly activated by fibrillar Aß (fAß), can both enhance clearance and induce inflammation. In addition, complement activation dependent excessive synapse pruning occurs in models of AD and other neurological disorders, and is postulated to contribute to the loss of cognition. Our data demonstrate that pharmacologic inhibition or genetic deletion of C5aR1, a receptor for the complement activation proinflammatory fragment, C5a, suppresses cognitive loss in mouse models of Alzheimer's disease/amyloidosis. This study proposes to investigate the effect of a C5a receptor antagonist on inflammation- and clearance-related gene expression (using single cell RNA-seq to evaluate multiple cell types affected), protein expression and synaptic density (via super resolution microscropy) in order to determine if C5aR1 plays a direct or indirect role in neuronal damage and whether C5aR1 antagonists may be promising therapeutic candidates for future clinical trials in humans to prevent cognitive impairment.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
