L-serine-enriched diet restores impaired adult neurogenesis in the hippocampus of 3xTg-AD mice

Background Altered adult neurogenesis occurs in Alzheimer's disease (AD) in humans and rodent models, though the mechanisms remain unclear. L-serine, a non-essential amino acid critical for cell proliferation and survival, is produced by neuroepithelial cells and radial glia in the developing brain, and by astrocytes and neural precursors in the adult brain. Its production is altered in AD, particularly in the hippocampus. Objective To determine whether reduced L-serine availability contributes to impaired adult neurogenesis in AD. Methods We examined the expression of phosphoglycerate dehydrogenase (PHGDH), an enzyme in L-serine biosynthesis, in neural stem cells (NSCs) of mouse and human dentate gyrus (DG). Adult neurogenesis was assessed by quantifying proliferating neural precursors and immature neurons in 7- and 12-month-old 3xTg-AD mice and age-matched controls. Mice received an L-serine-enriched diet for 4 or 8 months, after which plasma serine levels, neurogenesis markers, and amyloid pathology were evaluated. Results PHGDH was expressed by NSCs in the mouse DG and by cells in the subgranular zone (SGZ) of the human DG showing radial morphology typical of rodent NSCs. Twelve-month-old 3xTg-AD mice showed a significant reduction in proliferating (PCNA-positive) precursors and immature (DCX-positive) neurons in the DG relative to controls. L-serine supplementation significantly raised plasma L- and D-serine levels and partially rescued neurogenesis deficits in 3xTg-AD mice, without affecting amyloid pathology. Conclusions We suggest that impairment of L-serine metabolism and the resulting reduction in D-serine availability contributes to impaired adult neurogenesis, potentially via reduced survival of newborn neurons in the DG of 3xTg-AD mice.