Pascente, R. | bioRxiv Science

bioRxiv2025

Brain infiltrating T cells mediate microglial dysregulation and neuronal loss following SAH

The contribution of T cells to neuroinflammation after aneurysmal subarachnoid hemorrhage (SAH) remains poorly understood. Using a murine pre-chiasmatic injection model of SAH we demonstrate that T cell infiltration into the brain modulates microglial activation and promotes neuronal death. Targeted transcriptomic profiling revealed a sustained neuroimmune response at 7 days post injury (dpi) characterized by a major involvement of T cells and microglia activation. Immunohistochemistry confirmed focal CD3+ T cell infiltration, predominantly CD4+, in the brain at the site of blood injection (BI), choroid plexus and meninges in SAH mice at 3- and 7-dpi. This temporal pattern was also observed in the CSF of a human SAH cohort. T cell presence spatially correlated with regions of microglial reactivity and neuronal loss. Notably, CD3-knockout mice exhibited reduced microglial activation and preserved neuronal viability. These findings identify T cells as key amplifiers of post-SAH neuroinflammation and neuronal damage. Targeting T cell-microglia crosstalk may represent a novel therapeutic avenue for SAH. Summary statementThis study shows that brain T-cell infiltration after subarachnoid hemorrhage drives microglial activation and neuronal loss in mice, with similar patterns observed in patients. Data indicate T cells as key mediators of post-injury neuroinflammation with therapeutic implications.

neuroscience↗

bioRxiv2022

SUMO2 Protects Against Tau-induced Synaptic and Cognitive Dysfunction

Abnormal intracellular accumulation of Tau aggregates is a hallmark of Alzheimers disease (AD) and other Tauopathies, such as Frontotemporal dementia (FTD), which can be caused by mutations of Tau. Mutated and pathological Tau can undergo a range of post-translational modifications (PTMs) that might trigger or modulate disease pathology. Recent studies indicate that modification of wild type Tau by Small ubiquitin-like modifier SUMO isoform 1 (SUMO1) controls Tau hyperphosphorylation and aggregation, suggesting that SUMOylation acts as a central regulator of Taus biochemical properties. Besides SUMO1, Tau is modified by SUMO2/3, however the consequences of this modification have not been investigated. Here, using viral approaches on primary hippocampal neurons, transgenic mice expressing mutant Tau and SUMO2, and iPSC-derived neurons from FTD patients, we evaluated whether SUMO2/3 conjugation modifies the neurodegenerative disease pathology associated with the aggregation-prone mutant Tau P301L, P301S, and R406W variants. We found that mutant forms of Tau are targets of SUMO2/3, and SUMO2/3 conjugation is neuroprotective. Importantly, expression of mutant Tau is accompanied by a significant reduction of SUMO2/3 conjugation levels, and restoring levels of SUMO2 reduces mutant Tau aggregation and phosphorylation in all model systems Furthermore, overexpression of SUMO2 restores levels of pre- and post-synaptic markers, associated with a complete rescue of the LTP and memory deficits in transgenic mice expressing mutant Tau. These findings bring to light the potential therapeutic implication of manipulating SUMO conjugation to detoxify Tau through PTM-based approaches.

neuroscience↗