Photobiomodulation mitigates blood–brain barrier disruption in APP/PS1 mouse model of Alzheimer’s disease by activating the AMPK pathway

Photobiomodulation (PBM), which utilizes specific light wavelengths to regulate cellular metabolism, signal transduction, and gene expression, has emerged as a promising intervention for enhancing cognitive function in Alzheimer's disease (AD). The blood-brain barrier (BBB) plays a critical role in protecting the central nervous system, and its dysfunction is a major contributor to AD pathogenesis. Although PBM has shown therapeutic potential, its effects on BBB integrity and the underlying mechanisms remain unclear. Six-month-old female APP/PS1 transgenic mice were subjected to PBM intervention (808 nm, 20 mW/cm2) for six weeks. Cognitive function was assessed using behavioral tests, while biochemical and histological analyses were conducted to evaluate BBB integrity, β-amyloid (Aβ) deposition, and protein expression related to tight junction proteins (TJs). In vitro, an inflammatory model was established by treating brain microvascular endothelial cells (bEnd.3) with lipopolysaccharide (LPS) to induce an inflammatory response, and the mechanisms of PBM were further explored by analyzing mitochondrial function. PBM significantly improved cognitive deficits and anxiety-like behaviors in AD mice. It enhanced BBB integrity by upregulating the TJs Occludin, Claudin-5, and ZO-1, while also facilitating Aβ clearance via the low-density lipoprotein receptor-related protein 1 (LRP1) pathway and microglial phagocytosis, thereby reducing Aβ accumulation in the brain. Mechanistically, PBM attenuated apoptosis and mitochondrial oxidative stress while promoting mitochondrial energy metabolism. Notably, PBM markedly increased phosphorylated AMPK (p-AMPK) levels in the brains of AD mice. In vitro, the protective effects of PBM on BBB integrity were substantially diminished upon AMPK inhibition, confirming that PBM exerts its neuroprotective effects through the activation of the AMPK pathway. This study demonstrates that PBM enhances BBB integrity and mitigates Aβ pathology in AD mice by activating the AMPK signaling pathway, underscoring its potential as a novel, non-invasive therapeutic strategy for AD.