Loss of Mitochondrial Tusc2/Fus1 Triggers a Brain Pro-Inflammatory Microenvironment and Early Spatial Memory Impairment

TL;DR

Loss of a mitochondrial protein in mice causes brain inflammation and memory problems, suggesting new ways to treat cognitive decline.

Contribution

The study reveals a novel link between mitochondrial Tusc2 loss, brain inflammation, and early memory impairment in mice.

Findings

Tusc2−/− female mice show increased pro-inflammatory immune responses in the brain.

Tusc2−/− mice exhibit Tusc2- and sex-specific changes in proteins related to brain plasticity and calcium signaling.

Reduced anti-inflammatory immune cells in Tusc2−/− brains suggest impaired regulation of inflammation.

Abstract

Brain pathological changes impair cognition early in disease etiology. There is an urgent need to understand aging-linked mechanisms of early memory loss to develop therapeutic strategies and prevent the development of cognitive impairment. Tusc2 is a mitochondrial-resident protein regulating Ca2+ fluxes to and from mitochondria impacting overall health. We previously reported that Tusc2−/− female mice develop chronic inflammation and age prematurely, causing age- and sex-dependent spatial memory deficits at 5 months old. Therefore, we investigated Tusc2-dependent mechanisms of memory impairment in 4-month-old mice, comparing changes in resident and brain-infiltrating immune cells. Interestingly, Tusc2−/− female mice demonstrated a pro-inflammatory increase in astrocytes, expression of IFN-γ in CD4+ T cells and Granzyme-B in CD8+T cells. We also found fewer FOXP3+ T-regulatory cells and Ly49G+ NK and Ly49G+ NKT cells in female Tusc2−/− brains, suggesting a dampened anti-inflammatory response. Moreover, Tusc2−/− hippocampi exhibited Tusc2- and sex-specific protein changes associated with brain plasticity, including mTOR activation, and Calbindin and CamKII dysregulation affecting intracellular Ca2+ dynamics. Overall, the data suggest that dysregulation of Ca2+-dependent processes and a heightened pro-inflammatory brain microenvironment in Tusc2−/− mice could underlie cognitive impairment. Thus, strategies to modulate the mitochondrial Tusc2- and Ca2+- signaling pathways in the brain should be explored to improve cognitive health.

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