Transcranial near-infrared therapy restores synaptic resilience by reshaping signaling landscapes in sleep-deprived tauopathy.

Chronic sleep deprivation (SD) is a prevalent and modifiable risk factor that accelerates neurodegeneration and exacerbates cognitive decline in Alzheimer's disease (AD). Here, we demonstrate that 808 ​nm transcranial near-infrared (tNIR) therapy reverses cognitive impairment in tauopathy mice subjected to chronic SD through multi-level molecular and circuit restoration. Behavioral and electrophysiological assessments revealed that tNIR reinstated hippocampal-dependent memory and long-term potentiation. Multi-omics profiling uncovered that tNIR orchestrates a coordinated remodeling of GPCR-cAMP-CREB signaling, synaptic vesicle cycling, and excitatory-inhibitory neruotransmission, encompassing glutamatergic, GABAergic, and retrograde endocannabinoid pathways. Lipidomic analyses identified selective remodeling of membrane microdomains, with phospholipids such as MGDG(16:0/20:2) and LPC(20:4) positively correlating with genes governing calcium signaling, vesicle dynamics, and synaptic plasticity. In parallel, tNIR suppressed stress-associated lipid-gene networks linked to oxidative damage and apoptosis. Proteomic data revealed upregulation of antioxidant enzymes (e.g., SOD2) and suppression of pro-apoptotic mediators, supporting mitochondrial resilience. Collectively, these multi-omics signatures converge on restored neurotransmitter turnover, stabilized excitatory-inhibitory balance, and reestablished a synaptically supportive microenvironment. This study provides the first evidence that tNIR therapy counteracts the compounded effects of chronic sleep deprivation and tau pathology on memory, thereby establishing a clinically relevant dual-burden framework for investigating sleep-neurodegeneration interactions. Our findings position tNIR as a non-invasive, systems-level neuromodulatory approach for mitigating sleep-related cognitive vulnerability in neurodegeneration.