Short Polysialic Acid Counteracts Age-Related Synaptic and Cognitive Deficits

Abstract Impaired activity of glutamate transporters, elevated concentration of extrasynaptic glutamate and hyperactivity of extrasynaptic GluN2B-containing NMDA receptors are common features in aging and several neurological conditions, including Alzheimer’s disease (AD). Previous studies revealed that polysialic acid (polySia), a glycan predominantly carried by the neural cell adhesion molecule NCAM, inhibits extrasynaptic NMDA receptors and supports synaptic plasticity in healthy adult brains. Moreover, intranasal delivery of polySia with the degree of polymerization 12 (NANA12) rescued synaptic plasticity and cognitive functions in models of tauopathy and amyloidosis associated with AD. Here, we comparatively studied the effects of NANA12 in young (4 months) old (26 months) and very old (29 months) mice. Strikingly, NANA12 promoted cognitive flexibility in attentional set-shifting (ASST) tests and spatial memory in the Barnes maze in very old mice. To capture fine-grained effects undetectable by conventional methods, we introduced a novel trial-wise data analysis approach for evaluating ASST performance. The observed cognitive improvements were not due to changes in the size of hippocampal memory engrams, visualized by c-Fos immunolabeling after reactivation of spatial memory in the probe trial. Five-day treatment with NANA12 did not affect neuronal structure (MAP2 levels), expression of senescence (lipofuscin) or neuroinflammation (microglial Iba1) markers, activation of BDNF receptors (p-TrkB) or expression of endogenous polySia in the hippocampus of very old mice. However, cognitive improvements correlated with the normalized size of CD68 + microglial lysosomes and reduced amounts of pre- and postsynaptic proteins at these structures. Thus, our data demonstrate the potential of short polySia to reduce synaptic phagocytosis and restore key cognitive functions attenuated in aging.