Neurons ensheathed by perineuronal nets are prone to hyperphosphorylation of tau protein in the hibernating Syrian hamster brain

Abstract

Abstract Perineuronal nets (PNNs) are a specialized form of neuronal extracellular matrix that often ensheath highly active cells, such as parvalbumin-positive (PV+) interneurons. Net-bearing neurons have been shown to be devoid of pathological aggregates of hyperphosphorylated tau protein (p-tau), suggesting they may serve neuroprotective functions. P-tau is a major hallmark of tauopathies like Alzheimer’s disease (AD) but is also naturally present in the brains of hibernating mammals during the torpor phase. However, the relationship between PNNs and p-tau in both pathological and physiological contexts remains unclear. In this study, we examined the association between PNNs, PV, and p-tau in the neocortex of hibernating Syrian hamsters. We observed consistent PNN expression across euthermic and torpid states. Unexpectedly, PNN-enwrapped neurons showed a higher prevalence of p-tau (82%) compared to the overall neuronal population (60%) during torpor. Similarly, PV+ interneurons displayed a high prevalence of p-tau (78%). These findings suggest that PNNs do not prevent tau hyperphosphorylation under physiological conditions like hibernation, in contrast to their potential neuroprotective role in AD pathology. Instead, specific neuronal subsets, such as PNN-enwrapped PV+ interneurons, are likely to exhibit p-tau during torpor. Further analysis of the interplay between p-tau, PNNs, and PV+ interneurons may therefore reveal adaptive strategies for neuronal protection and metabolic regulation, with implications for neurodegeneration and brain metabolic stress.