Improved NMDA Receptor Activation by the Secreted Amyloid-Protein Precursor-α in Healthy Aging: A Role for D-Serine?

Abstract

Impaired activation of the N-methyl-D-aspartate subtype of glutamate receptors (NMDAR) by D-serine is linked to cognitive aging. Whether this deregulation may be used to initiate pharmacological strategies has yet to be considered. To this end, we performed electrophysiological extracellular recordings at CA3/CA1 synapses in hippocampal slices from young and aged mice. We show that 0.1 nM of the soluble N-terminal recombinant fragment of the secreted amyloid-protein precursor-α (sAPPα) added in the bath significantly increased NMDAR activation in aged but not adult mice without impacting basal synaptic transmission. In addition, sAPPα rescued the age-related deficit of theta-burst-induced long-term potentiation. Significant NMDAR improvement occurred in adult mice when sAPPα was raised to 1 nM, and this effect was drastically reduced in transgenic mice deprived of D-serine through genetic deletion of the synthesizing enzyme serine racemase. Altogether, these results emphasize the interest to consider sAPPα treatment targeting D-serine-dependent NMDAR deregulation to alleviate cognitive aging.

Viral vector-mediated upregulation of serine racemase expression in medial prefrontal cortex improves learning and synaptic function in middle age rats

“…In the aging brain, D-serine levels and NMDAR-mediated synaptic transmission are reduced [33][34][35][36][37][38][39], whereas supplementation with exogenous D-serine in aged rats [34] or mice with low D-serine release due to astrocytic mutations [69] normalize hypofunctional NMDAR responses. Moreover, the beneficial effects of sAPPα, a secreted form of amyloid precursor protein generated by the nonamyloidogenic pathway, on NMDAR-mediated transmission in hippocampal slices of aged mice are partially mediated by the D-serine pathway, as evidenced by an attenuation of these enhancing effects in SR knockout mice [70]. These beneficial effects of D-serine have translated to amelioration of cognitive function in elderly as well.…”

Serine racemase expression profile in the prefrontal cortex and hippocampal subregions during aging in male and female rats

“…A recent study found that secreted amyloid protein precursor-α (sAPPα), derived from the cleavage of amyloid protein precursor, notably enhances NMDA receptor function exclusively in aged animals, restoring impaired long-term potentiation (LTP) associated with aging. Yet, this effect is significantly reduced in SR knockout mice [ 47 ]. Overall, the results suggest that D-serine is crucial for the activation of NMDA receptors and NMDA receptor-mediated synaptic plasticity.…”