Modulation of Brain D-Serine Metabolism and Signaling in Aging and Alzheimer's Disease - Alzheimer’s disease (AD) is an age-related progressive neurological disorder characterized by cognitive decline, synaptic dysfunction, and neurodegeneration. Despite extensive research, therapeutic options remain limited. Cognitive decline and neurodegeneration in AD are strongly associated with dysregulated N-methyl-D-aspartate receptor (NMDAR) signaling, where both excess and deficiency of D-serine, a co-agonist of NMDARs, contribute to pathology. Serine racemase (SRR), the enzyme responsible for D-serine synthesis, and D-amino acid oxidase (DAO), which metabolizes D-serine, are critical regulators of this pathway. However, their roles in brain aging and AD remain poorly understood. This project aims to elucidate the molecular and cellular mechanisms under- lying cognitive decline in aging and AD, focusing on SRR and DAO in hippocampal learning, memory, and NMDAR signaling across aging and AD stages, using rodent models and human tissue samples. Our hypothesis is that aging and AD impact D-serine metabolism through distinct mechanisms, impairing NMDAR function and cognition. In aging, dysfunction arises from reduced neuronal SRR expression, while in AD, it is driven by an increase in glial SRR and compensatory upregulation of DAO expression. This results in a disruption in D-ser- ine’s potentiation of NMDARs, worsening cognition and neuropathology. Aim 1 investigates the roles of neuronal and glial SRR in TgF344-AD rats. We predict that a shift from predominantly neuronal to glial SRR expression is key to AD pathology. Using viral vectors, we will modulate SRR expression in neurons and glial cells of the hippocampus, followed by behavioral testing, molecular assays, and electrophysiological recordings to examine NMDAR activity and pathology. We hypothesize that increasing neuronal SRR will rescue aging non-Tg rats from cognitive decline and enhance synaptic NMDAR activity during learning, whereas upregulating glial SRR will exacerbate AD pathology in TgF344-AD rats by promoting excessive extrasynaptic NMDAR activation. Aim 2 investigates DAO’s role in memory, NMDAR signaling, and AD pathology. DAO is minimally expressed in corticolimbic regions but may increase in response to AD as a compensatory mechanism against excessive NMDAR activity. We will assess DAO expression in human AD specimens and apply viral modulation of DAO in the hippocampus of TgF344-AD rats to evaluate its effects on behavior and neuropathology. We predict that DAO induction in TgF344-AD rats will reduce neurodegeneration by lessening extrasynaptic NMDAR activity, while overexpression in non-Tg rats will impair cognition and synaptic NMDAR function. These studies will elu- cidate the roles of SRR and DAO in cognitive decline, NMDAR dysfunction, and AD neurodegeneration. By developing molecular tools to investigate these pathways, this research could improve diagnosis of age- and AD-related memory loss while uncovering therapeutic targets to restore balance to NMDAR signaling and slow AD progression. This project also supports the expansion of the PI’s research program to explore AD processes and pathology with supportive mentors within a highly collaborative and growing AD research consortium.
