A COMPLEX ROLE OF ASTROGLIAL CALCINEURIN IN ALZHEIMER'S DISEASE: FROM NEUROINFLAMMATION TO PROTEIN DYSHOMEOSTASIS

Alzheimer’s disease (AD) urgently requires novel therapeutic targets. Neuroinflammation and protein dyshomeostasis are central to its pathogenesis. During AD progression, astrocytes exhibit overactivation of the calcineurin (CN)–NFAT pathway, promoting reactive gliosis and inflammation. This study investigated whether astrocyte-specific deletion of the regulatory CN subunit CNB1 (CAN-KO) mitigates AD-related cognitive deficits, neuropathology, and neuroinflammation. We generated acute and chronic AD mouse models with astrocytic CNB1 ablation, and used biochemical and functional assy. In the acute model, conditional ACN-KO prevents recognition memory from Aβ oligomers induced toxicity. In the chronic model, a tamoxifen astrocyte-specific CNB1 knockout was inducted in 3xTg-AD mice. These mice showed preserved spatial memory and cognitive flexibility, alongside reductions in amyloid plaques, neurofibrillary tangles, reactive gliosis, and neuroinflammation.
We further explored the molecular interplay between CN, protein synthesis, and inflammation in primary cortical and immortalized hippocampal astrocytes. Under physiological conditions, CN interacts with eIF2α, preventing its phosphorylation and sustaining protein synthesis. Pro-inflammatory stimuli, such as TNF/IFNγ and LPS, activate the Ca²⁺-dependent CN–NFAT pathway, leading to translational repression and increased eIF2α phosphorylation. In AD, CN overactivation appears to shift its interaction from eIF2α to NFAT, driving both neuroinflammation and protein synthesis impairment. Astrocyte-specific CNB1 deletion in 3xTg-AD mice abolishes CN catalytic activity and NFAT activation while preserving CNA–eIF2α interaction, maintaining protein synthesis, reducing neuroinflammation, and preventing cognitive decline and neuropathology.
Therefore, targeting astrocytic calcineurin represents valuable strategy to prevent neuroinflammation, to preserve protein homeostasis, hence prevent/or cure AD pathology.