Yuanzi-Shichangpu herb pair ameliorates mitochondrial energetics and restores blood-brain barrier integrity in Alzheimer's disease through the HIF-1α/GSK3β-Nrf2/PGC-1α axis.

Alzheimer's disease (AD) presents a significant global therapeutic challenge. Growing evidence underscores the critical role of blood-brain barrier (BBB) disruption and cerebral energy metabolism dysfunction in driving AD pathogenesis, often forming a vicious cycle of "mitochondrial impairment-BBB damage-neuronal degeneration." The classic herbal pair of Yuanzhi (YZ) and Shichangpu (SCP) has a long history of use in cognitive disorders within Traditional Chinese Medicine, yet an integrated understanding of how this herb pair systemically modulates key AD pathologies-particularly neurovascular unit integrity and bioenergetic homeostasis remains lacking. This study aimed to elucidate the multi-faceted neuroprotective effects of the YZ-SCP herb pair and its underlying molecular mechanisms in AD models. Both an in vivo D-gal/AlCl3-induced AD rat model and an in vitro Aβ-injured bEnd.3 brain microvascular endothelial cell model were employed. Evaluations included cognitive behavior, hippocampal histopathology, BBB integrity, mitochondrial ultrastructure and function, cerebral energy metabolism profiling, and mechanistic analysis focusing on the HIF-1α/GSK3β-Nrf2/PGC-1α signaling axis. The YZ-SCP herb pair exhibited enhanced effects in improving spatial learning and memory, ameliorated hippocampal neuronal damage, and restored BBB integrity by upregulating tight junction proteins (ZO-1, Occludin, Claudin-5) and VE-cadherin. Mechanistically, it suppressed the aberrant HIF-1α/GSK3β pathway, activated the PGC-1α/Nrf2/SOD2 antioxidant axis, and restored mitochondrial bioenergetics, evidenced by recovered ATP production, membrane potential, and NAD+/NADH homeostasis. Energy metabolomics further demonstrated a systemic remodeling of the hippocampal metabolic profile, notably in the TCA cycle. In vitro studies confirmed that YZ-SCP-containing serum dose-dependently improved endothelial mitochondrial function and reduced oxidative damage by modulating the same signaling cascades.