Catestatin regulation of tauopathy and its therapeutic potentials

The National Institute on Aging awarded the Veterans Medical Research Foundation of San Diego $811,250 on September 15, 2025, under the Aging Research program (CFDA 93.866) to investigate catestatin regulation of tauopathy and its therapeutic potential in Alzheimer's disease.

The research examines how catestatin, a peptide derived from chromogranin A, modulates tau phosphorylation, tau aggregation, and microglial activation in tauopathy models. Preliminary work in PS19 mice demonstrated that catestatin exposure decreases tau pathology markers and reduces hippocampal microglial activation coupled with decreased inflammatory chemokine and cytokine concentrations. The project will test dose-dependent effects of catestatin on tauopathy phenotypes and establish mechanistic pathways underlying catestatin's neuroprotective effects. This is a Project Grant assistance type with a period of performance through August 31, 2027, and place of performance in California.

Abstract

Alzheimer's disease (ad) is a neurodegenerative disease characterized by the progressive decline of memory and cognitive functions associated with neuronal loss. Formation of extracellular amyloid beta (AB) plaques containing insoluble B-amyloid, intracellular neurofibrillary tangles (NFTS) composed of hyperphosphorylated TAU, and microglial dysfunction leading to neuroinflammation are the major hallmarks of ad. The existing FDA approved drugs offer limited effects on cognitive improvement and ad remains inexorable and incurable. Therefore, there is an urgent need for novel discoveries on therapeutic targets. Chromogranin a (CGA) is overexpressed in ad and corticobasal degeneration (CBD) frontal cortices as well as in CORTEX of 9-month-old PS19 mice. In contrast, catestatin (CST: HCGA352-372), a pleiotropic peptide derived from CGA, is significantly reduced in primary (CBD and PSP, progressive supranuclear palsy) and secondary (ad) tauopathy brains as well as in PS19 brain. Using mini-mental state examination score, we found that a low concentration of CST is associated with the worst prognosis in both ad CORTEX and hippocampus. CST also caused decreased phosphorylation of TAU and TAU aggregation in vivo in PS19 mice as well as decreased seeding in organotypic slice culture. In addition, CST caused decreased activation of hippocampal microglia coupled with decreased concentration of inflammatory chemokines/cytokines in PS19 brain (CORTEX). Furthermore, we found exposure of CST in PS19 brain after intraperitoneal and subcutaneous administration of CST, indicating that the above effects of CST in PS19 mice are indeed direct effects. We have developed three specific aims to fulfil our hypotheses. Aim I: determine CST-induced amelioration of tauopathy phenotypes. Although our preliminary results are convincing and statistically powered, in this aim, we will (I) test dose-dependent effects of CST in improvement in behavioral and cognitive deficits in PS19 mice (pro-active and reactive cohort), (II) evaluate dose-dependent effects of CST on neurofibrillary tangles (NFTS), synapse, synaptic vesicles, and mitochondrial health; and (III) dose-dependent effects on phosphorylation of TAU. Aim II: determine the mechanisms underlying CST-induced amelioration of tauopathy. In this aim, we will (I) run RNA SEQ analyses to assess CST-induced differentially expressed genes in PS19 brain (CORTEX and hippocampus); (II) examine whether CST ameliorates tauopathy by reducing neuroinflammation in PS19 brain and in primary microglia cells. (III) evaluate whether CST inhibited catecholamine secretion is one of the mechanisms of action. Aim III: evaluate the admet (absorption, distribution, metabolism, excretion, and toxicology) properties of CST. These studies will be performed in collaboration with DR. Daniel B. Kassel, founder & CEO, scianalytical strategies, INC. SAN diego, CA. Impact: successful completion of the proposed studies will help determine if CST can be developed as a potential therapy against the multifactorial disease ad/tauopathy.