Ptprd deficiency promotes tau hyperphosphorylation and impairs cognitive function in aged mice.

Abstract

Background: Tau phosphorylation is a tightly regulated process that ensures proper neuronal function. Indeed, hyperphosphorylation of tau closely contributes to neuronal dysfunction leading to neurodegenerative diseases, including tauopathies, which are characterized by excessive and aberrant tau phosphorylation and cognitive decline. Therefore, it is important to understand how to regulate its phosphorylation. In this regard, the protein tyrosine phosphatase receptor delta (PTPRD) has been genetically implicated in tau pathology in humans, but the mechanisms underlying its role in tau regulation remain unclear. This study investigates the impact of Ptprd deficiency on tau phosphorylation, cognitive function, neuroinflammation, and synaptic markers in aging mice.

Results: Mice lacking Ptprd showed increased tau phosphorylation at multiple sites associated with its pathological aggregation. This effect was accompanied by the activation of the tau-related kinase Abl1, particularly in the hippocampus. Behavioral assessments revealed significant impairments in learning and memory, demonstrating the functional impact of these alterations. Moreover, Ptprd knockout mice showed increased microgliosis in both the entorhinal cortex and the hippocampus, suggesting a pro-inflammatory response. Furthermore, the synaptic protein PSD95 was also reduced in the cortex, indicating potential synaptic dysfunction.

Conclusions: The loss of Ptprd leads to increased tau phosphorylation, cognitive impairments, microgliosis, and synaptic alterations in older mice. Our findings also suggest that Ptprd plays a critical role in maintaining tau homeostasis through the Abl1 kinase. This indicates a new potential therapeutic approach for tauopathies, where PTPRD could serve a protective role against tau-related pathologies and may act as a key modulator in disease progression.