Hippocampal Hap1 downregulation exacerbates Alzheimer's disease-related neuropathology and impairs glucocorticoid receptor nuclear translocation in APP/PS1 mice

Although impaired nuclear translocation of glucocorticoid receptor (GR) contributes to hippocampal vulnerability in Alzheimer's disease (AD), its regulatory mechanisms remain poorly understood.Here, we identify Huntingtin-associated protein 1 (Hap1) as a critical regulator of GR nuclear translocation in the hippocampus. Specifically, Hap1 expression progressively declines in the APP/PS1 mouse hippocampus with aging and pathological progression. Hippocampal Hap1 knockdown induces cognitive deficits and synaptic loss, manifested as reduced dendritic complexity and spine density alongside impaired long-term potentiation (LTP), while exacerbating Aβ deposition in APP/PS1 mice. Crucially, Hap1 deficiency promotes GR ubiquitination and proteasomal degradation and, more critically, disrupts ligand-dependent GR nuclear translocation, thereby impairing GR-dependent BDNF transcription. Additionally, Hap1 knockdown elevates corticosterone levels and induces depressive-like behaviors, confirming hypothalamic-pituitary-adrenal (HPA) axis dysregulation. Our results establish disruption of Hap1-mediated GR nuclear translocation as a key pathomechanism linking intracellular transport defects to synaptic failure in AD, suggesting Hap1 modulation as a potential therapeutic avenue.