Neural stem cell transplantation attenuates cognitive decline and neuroinflammation in a mouse model of Alzheimer’s disease with chronic cerebral hypoperfusion

Alzheimer's disease (AD) and chronic cerebral hypoperfusion (CCH) frequently coexist in aging populations, synergistically aggravating neurodegeneration. To assess the therapeutic potential of stem cell interventions, an AD + CCH mouse model was generated by combining APP/PS1 mice with bilateral common carotid artery stenosis. Neural stem cells (NSCs) or induced pluripotent stem cells (iPSCs) were transplanted into the lateral ventricles at 5 months of age. Behavioral testing, Nissl staining, Western blotting, and immunofluorescence were conducted at 9 and 12 months to evaluate cognition, neuronal survival, cell death pathways (LC3-II, cleaved caspase-3, NLRP3), glial polarization, and neurotrophic/synaptic markers (BDNF, VEGF, VAChT, PSD95). CCH exacerbated AD-related cognitive deficits, neuronal loss, and activation of autophagic, apoptotic, and pyroptotic pathways, accompanied by enhanced M1 microglial polarization, astrogliosis, and downregulation of BDNF and VAChT. NSCs transplantation significantly improved cognitive performance, preserved neuronal integrity, attenuated glial activation, and restored neurotrophic and synaptic protein expression, characterized by increased BDNF, VEGF, and PSD95 levels and partial recovery of VAChT. In contrast, iPSCs transplantation failed to exert comparable effects. These findings demonstrate that NSCs, but not iPSCs, mitigate AD + CCH-induced neuropathology by re-establishing the balance between inflammatory, neurotrophic, and synaptic signaling, supporting NSCs as a promising therapeutic approach for AD with vascular comorbidity.