PeptiMem: Uncovering Sex-Specific Memory Restoration Through Chromogranin A-Derived Peptides in Alzheimer's Disease

Overview

Alzheimer’s disease (AD) affects nearly 55 million people worldwide and is characterized by progressive cognitive decline associated with tau neurofibrillary tangles and β-amyloid plaques. Although AD disproportionately affects females, sex-specific therapeutic strategies remain largely unexplored. Chromogranin A (CgA)-derived peptides catestatin (CST; hCgA352-372) and pancreastatin (PST: hCgA250-301) have been found to differentially regulate neuroinflammatory and synaptic pathways, suggesting their efficacy in treating tauopathies. To address this gap, this study investigated sex-dependent cognitive modulation mediated by CST and PST in CgA-knockout (CgA-KO) and PS19 mouse models. Mice (n=5–8/sex/treatment) were treated with intraperitoneal saline, CST (1 µg/g body weight), PST (0.7 µg/g body weight), or CST+PST for 10 weeks. Working memory (spontaneous alternation) and long-term spatial recognition memory (Y-maze novel arm exploration) were assessed longitudinally to quantify restoration of memory potential. For CgA-KO mice, both peptides improved cognition relative to saline; females exhibited stronger responses to CST treatment, whereas males exhibited stronger responses to PST-containing treatments. In contrast, under tau pathology, CST significantly restored cognition in both sexes (p<0.05), while PST caused detrimental effects to memory. Furthermore, a novel two-phase computational framework was engineered, integrating cross-validated regularized treatment effect modeling with a residual machine-learning classifier (AUC=0.91), to confirm CST as the most effective intervention in tauopathy and predict responders to AD treatments given healthy, sex-specific baseline conditions. Collectively, these findings identify CST as a sex-aware therapeutic candidate and highlight the importance of incorporating biological sex, disease context, and computational modeling into peptide-based AD treatment strategies, advancing precision neurotherapeutics.

Competition history

• CSEF 2026 Medicine & Physiology (Track 2) (Senior Division) · Entry S-21-16

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