Therapeutic Potential of Naive Hair Follicle Stem Cells in Alzheimer’s Disease: A Comprehensive Evaluation of Neuroprotection and Neurogenesis

Background: As a highly prevalent neurological condition, Alzheimer’s disease (AD) imposes considerable economic pressure on global societies. Its core pathological feature is progressive degeneration within the central nervous system (CNS), a feature which establishes it as the leading trigger for dementia worldwide. Currently available therapies for AD are largely palliative and lack restorative efficacy. While stem cell transplantation holds promise for brain regeneration, the shortage of transplantable neural stem cells and ethical constraints remains a significant limitation. Hair follicle stem cells (HFSCs) are easily accessible, proliferative, low immunogenicity, and free of ethical concerns, making them an ideal candidate for neurodegenerative disease therapy. However, the application of naive, unmodified HFSCs in AD therapy has not been thoroughly explored. In contrast to our previous study using NGF-modified HFSCs, the present study used unmodified naive HFSCs to systematically evaluate their therapeutic effects in AD rats, focusing on neurogenesis, synaptic protection, and microglial polarization. Therefore, the present assessment sought a more complete understanding of HFSCs’ intrinsic therapeutic potential. Methods: We induced AD in rats via intrahippocampal injection of Aβ 1 – 4 2 . Fourteen days post-modeling, HFSCs were stereotaxically transplanted into the hippocampal region of AD rats. Learning and memory were assessed using the Morris water maze test, and neuronal damage was evaluated by Nissl staining. Synaptic protein levels were measured by Western blot and immunohistochemistry. The same staining approach was used to assess hippocampal neurogenesis and quantify Iba-1‑positive microglia. Moreover, qPCR was performed to measure mRNA levels of key pro‑inflammatory and anti‑inflammatory factors. Results: HFSCs transplantation not only markedly upregulated the synaptic proteins SYP and PSD-95, but also promoted neurogenesis and alleviated microglial overactivation in the AD rat hippocampus. Conclusion: HFSCs represent a highly promising therapeutic strategy for AD. When delivered via transplantation, these cells protect against synaptic and neuronal injury, boost hippocampal neurogenesis, and prevent abnormal overactivation of microglia in the cerebral tissues of AD model rats. Together, these results offer comprehensive preclinical proof of the intrinsic therapeutic potential of unmodified HFSCs, distinguishing it from previous studies using genetically modified cells and laying a solid foundation for future clinical translation.