Friday, April 26, 2024
4/26/2024
Alzheimer's disease (AD) is a debilitating age-progressive neurodegenerative disease defined by Aß accumulation, tau tangles, synaptic changes, and neuronal loss. Emotional and societal burdens elicited by AD are overwhelming; however, no cures are available. Deeper insight into the mechanisms causal for AD are urgently needed to enable the development of effective therapies. Extracellular vesicles (EVs) are a highly heterogeneous population of small membrane vesicles that are released into the extracellular space. EVs are implicated in AD but appear to have contradictory roles in neuroprotection and pathogenesis. One possibility is that unique populations of EVs have ascribed roles, but this model has not been tested. The six-transmembrane enzyme Glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5) acts at the cell surface in neurons to cleave the glycosylphosphatidylinositol (GPI)-anchor that tethers some proteins to the membrane. In adult animals, GDE2 activates the a-secretase ADAM10 and loss of GDE2 elicits a constellation of phenotypes associated with AD including increased Aß peptide production, synaptic loss, and neurodegeneration. Strikingly, GDE2 distribution and activity is disrupted in neurons of AD patient brain but not in healthy controls or in patients with Huntington's disease. Thus, GDE2 dysfunction shows some specificity to AD and could contribute to AD pathogenesis. Preliminary studies show that GDE2 is required for the release of microvesicles (MVs), a subpopulation of EVs that bud directly from the plasma membrane, and that GDE2-dependent MV release is neuronal activity-dependent. These observations viewed in context of GDE2 loss of function suggest the hypothesis that GDE2 regulates the activity-dependent release of a subpopulation of MVs that are required for neuronal survival, and that disruption of this mechanism in AD contributes to disease pathology. This proposal will test this hypothesis in three Aims. Aim 1 will define the mechanism of GDE2 activity-dependent MV release in neurons. Aim 2 will examine neuroprotective capabilities of MVs released by GDE2 and distinguish if neuroprotection is achieved through clearance of toxic components or through active pro-survival cargoes. Aim 3 will determine if GDE2 MV release is perturbed in AD through analysis of human postmortem tissues. Our studies are expected to provide new molecular and physiological insight into neuronal activity-driven mechanisms of MV biogenesis and could introduce fresh perspective on roles for MVs in AD pathophysiology.
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