IMPROVING MITOCHONDRIAL BIOENERGETICS MODULATES GLIAL STATES IN ALZHEIMER’S DISEASE

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, memory loss and neuronal dysfunction. Pathological accumulation of amyloid-b (Ab) and hyperphosphorylated tau proteins drives chronic neuroinflammation and glial cell dysregulation, ultimately contributing to neuronal injury and disease progression. Current approved therapies primarily target Ab aggregates or provide symptomatic relief, underscoring a critical need for therapeutic strategies that address disease-relevant cellular and molecular mechanisms. Importantly, growing evidence identifies mitochondrial dysfunction as a key early and prominent feature of AD, preceding significant Ab and tau accumulation and playing a critical role in disease onset and progression, suggesting mitochondrial-targeted interventions as a promising therapeutic strategy. We have developed a compound designed to improve mitochondrial bioenergetics. The aim of this study was to evaluate the therapeutic potential of our compound in modulating mitochondrial function, neuroinflammation, and gliosis in a mouse model of AD. Gliosis was characterized by flow cytometry using homeostatic and activation markers for microglia (TMEM119, P2RY12, TREM2) and astrocytes (ASCA-2, ICAM-1). Additionally, changes in neuroinflammation and glial cell morphology were assessed by immunohistochemical staining for microglia (IBA1), astrocytes (GFAP) and pro-inflammatory cytokines (TNF-a, IL-1b). Mitochondrial function in the hippocampus and cortex was measured using high-resolution respirometry. Treatment with our compound improved mitochondrial bioenergetic function and shifted glial activation states toward a less inflammatory profile compared to vehicle-treated controls. Overall, these findings support the potential of mitochondria-targeted interventions to modify disease-relevant mechanisms in AD.