Isoquercetin-ligustrazine co-polymorph attenuates hypoxia-accelerated Alzheimer's disease by suppressing PERK-CHOP-mediated ER stress.

Alzheimer's disease (AD), a neurodegenerative disorder predominantly affecting the elderly population, is frequently associated with hypoxic conditions, including obstructive sleep apnea and other age-related comorbidities. Arising from various pathological conditions, chronic hypoxia may contribute to the acceleration of AD progression. However, the precise mechanisms underlying hypoxia-induced cellular stress responses, particularly those involving ER stress and the PERK pathway, remain insufficiently explored. In this study, the therapeutic effects of a co-polymorph combining Isoquercetin and Ligustrazine (ILCP) on AD-related pathologies aggravated by chronic hypoxia were investigated. ApoE3/4 transgenic mice were exposed to hypoxic conditions for four weeks; results on oxidative stress levels, β-amyloid (Aβ) deposition, and neuronal apoptosis were assessed. Chronic hypoxia was found to intensify PERK pathway activity, elevate neuronal damage, and further aggravate AD-associated cognitive deficits. ILCP administration was associated with reduced PERK pathway activation, resulting in reduced oxidative stress, alleviated neuronal damage, and preserved synaptic plasticity. These findings support a role for PERK-CHOP signaling in hypoxia-driven AD pathology and suggest a potential link between ILCP treatment and modulation of this pathway.