Hippocampal neuronal progranulin mediates estrogen‑deficiency‑induced affective vulnerability and...

Perimenopausal women typically face a heightened risk of emotional disturbances, including anxiety and depression. The estrogen decline increases vulnerability to mood disorders, but the molecular mechanisms underlying stress resilience remain unclear. Here, we identify hippocampal neuronal progranulin (PGRN), a secreted neuroprotective glycoprotein, as a key regulator of affective resilience under estrogen-deficient conditions. Ovariectomy (OVX) reduces hippocampal neuronal PGRN expression and induces anxiety- and depression-like behaviors, whereas estradiol supplementation restores both PGRN levels and behavior. Adeno-associated virus (AAV)-mediated overexpression of PGRN alleviates affective deficits across OVX, 4‑vinylcyclohexene diepoxide (4-VCD)-induced ovarian failure, and natural aging models, while neuronal, but not microglial, Grn deletion exacerbates stress susceptibility. Mechanistically, PGRN restores lysosomal protease activity, normalizes autophagic flux, activates AMP-activated protein kinase (AMPK) phosphorylation, and rescues mushroom spine loss, thereby restoring cellular and synaptic homeostasis. Intracerebral recombinant PGRN rescues OVX‑induced behavioral deficits, and the blood-brain barrier (BBB)-permeable fragment granulin-E (GRN‑E) confers similar protection after systemic administration. Collectively, these findings demonstrate that hippocampal neuronal PGRN links estrogen signaling to lysosomal-autophagy pathways and synaptic plasticity, and highlight PGRN or its active fragments as promising therapeutic targets for perimenopausal depression and anxiety.