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

Abstract

Altered adult neurogenesis is reported in Alzheimers disease (AD) in humans and rodent models, though the mechanisms remain unclear. L-serine, a non-essential amino acid that plays a critical role in cell proliferation and survival, is produced by neuroepithelial cells and radial glia in the developing brain, as well as by astrocytes and neural precursors in the adult brain. Its production is altered in AD, particularly in the hippocampus. We sought to determine whether a deficiency of L-serine availability contributes to the reduced adult neurogenesis in AD. We confirm that phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme of the L-serine biosynthetic pathway, is expressed by neural stem cells (NSCs) of the mouse dentate gyrus (DG). We further report PHGDH expression in cells with somata located in the subgranular zone (SGZ) of the human DG and displaying the typical radial morphology associated with NSCs in rodents. We observed a significant decrease in the number of proliferating cells (proliferating cell nuclear antigen, PCNA+) as well as immature neurons (doublecortin, DCX+) in the DG of 12-month-old 3xTg-AD mice compared to their age-matched controls. Importantly, chronic dietary supplementation with a L-serine-enriched diet for 8 months significantly increased plasma L- and D-serine levels and partially rescued adult neurogenesis deficits in 3xTg-AD mice, while having no significant impact on the progression of amyloidosis. Our results suggest that chronic metabolic impairment in L-serine production, and the resulting shortage of D-serine, likely contributes to reduced survival of newborn neurons in the DG of 3xTg-AD mice.