Early involvement of D-serine in β-amyloid-dependent pathophysiology.

Abstract

The N-methyl-D-aspartate subtype of glutamate receptors (NMDAR) is a key regulator of brain plasticity encoding learning and memory. In addition to glutamate, NMDAR activation requires the binding of the co-agonist D-serine. The beta-amyloid (Aß) peptide which accumulates in Alzheimer's disease (AD), affects the D-serine-dependent NMDAR activation in vitro, but whether this alteration would significantly contribute to AD-related pathophysiology and memory deficits remains unclear. Herein, we report a decrease in the maximal pool of recruitable NMDAR and in the expression of NMDAR-dependent long-term potentiation together with impaired basal neurotransmission at CA3/CA1 synapses from hippocampal slices of 5xFAD mouse, an AD-related model with elevated Aß levels. The NMDAR synaptic impairments develop from 1.5 to 2 months of age with the initial rise of Aß and is correlated to a transient increase in D-serine levels. Deficits in working and spatial memories as well as cognitive flexibility then occurred in 10-12 months-old animals. Importantly, the NMDA-related synaptic deregulations (but not the altered basal neurotransmission) and behavioral impairments (working and cognitive flexibility) are prevented or reduced (spatial memory) in 5xFAD mice devoid of D-serine after genetic deletion of its synthesis enzyme serine racemase. Altogether, these results therefore provide in vivo evidence for the implication of D-serine at least in the early pathogenic signatures of AD driven by the increase in amyloid load suggesting that the recent proposal of preventive therapy of AD by administration of the precursor L-serine remains questionable.