TESC overexpression mitigates amyloid-β-induced hippocampal atrophy and memory decline

Genome-wide association studies (GWASs) have identified numerous candidate genes for human brain-imaging phenotypes; however, the biological relevance of many of these genes remains unconfirmed. This study aimed to investigate the causal relationships among tescalcin (TESC) (a GWAS-indicated gene), hippocampal volume, Alzheimer's disease (AD), and the underlying biological mechanisms.

Human transcriptional data were analyzed to confirm relative TESC expression in the hippocampus. In cell experiments, RNA-seq analysis was used to identify the potential biological pathways for TESC overexpression, and immunofluorescence imaging and cell viability assays were used to evaluate the effect of TESC overexpression on neuronal structure and survival. In animal experiments, the effects of TESC overexpression on hippocampal volume and cognitive function in normal mice and amyloid-β (Aβ)-induced AD mice were investigated by 9.4 T magnetic resonance imaging and behavioral tests. Underlying mechanisms were further assessed via western blotting and electrophysiological recordings.

Human transcriptional data demonstrated that TESC is primarily expressed in the hippocampus and neurons. TESC overexpression enhanced the viability of HT22 cells and reduced Aβ-induced cell death. In mouse models, Tesc-overexpressing mice revealed increased hippocampal volume, likely owing to enhanced cell viability and long-term potentiation (LTP), and reducing apoptotic- and oxidation-induced hippocampal damage. TESC overexpression could significantly mitigate Aβ-induced hippocampal atrophy and memory impairment, potentially by reducing Aβ-induced neuronal apoptosis and LTP weakening.

This study exemplifies the translation of GWAS findings into actionable biological knowledge and suggests that upregulation of TESC may offer a promising therapeutic strategy for AD.