Catestatin peptide ameliorates tauopathy and amyloidogenesis via adrenergic inhibition.

Abstract

Neurodegenerative disorders such as Alzheimer's disease (AD), Corticobasal Degeneration (CBD), and Progressive Supranuclear Palsy (PSP) are characterized by tau aggregation, neuroinflammation, and progressive cognitive decline. Although metabolic dysregulation and neuropeptide imbalance have been linked to these disorders, the functional consequences of this imbalance and its reversal remain poorly understood. Our previous work identified chromogranin A (CgA), the gene encoding a pro-hormone for several metabolic peptides, as a key regulator of tau pathology. Here, we investigate Catestatin (CST), a CgA-derived peptide, for its role in modulating tauopathy. We report marked reductions in CST levels and an increase in Pancreastatin (PST) in the hippocampus and cortex of AD brains, as well as in the frontal cortex of CBD and the basal ganglia of PSP. CST-supplementation in cortical neuronal cultures and organotypic slice cultures (OTSC) reduced Tau phosphorylation and aggregation. In vivo, CST administration to PS19 tauopathy mice decreased pathological Tau species, attenuated gliosis, improved cognitive function, and reduced amyloid burden and neuroinflammation in 5xFAD mice. Mechanistically, CST reduced epinephrine levels in PS19 and 5xFAD mice, suppressed Protein Kinase A hyperactivation in PS19 and OTSC, and revealed a link between CST deficiency, adrenergic stress signaling, tauopathy-mediated neurodegeneration, and the therapeutic potential of CST supplement.