Neural stem cell transplantation ameliorates mitochondrial dynamics-related protein abnormalities in a mouse model of Alzheimer’s disease with chronic cerebral hypoperfusion

Introduction Alzheimer’s disease (AD) frequently coexists with chronic cerebral hypoperfusion (CCH) and is associated with cognitive decline and neuropathology; however, treatments for this condition remain limited. Methods We established an AD+CCH murine model to compare the therapeutic effects of neural stem cells (NSCs) and undifferentiated induced pluripotent stem cells (iPSCs), with a focus on mito-chondrial dynamics and programmed cell death (PCD). APP/PS1 mice subjected to bilateral carotid artery stenosis received intracerebroventricular transplantation of NSCs or undifferentiated iPSCs. Cognitive function, amyloid-β (aβ) deposition, astrocyte activation, mitochondrial dynamics-associated proteins (DRP1, FIS1, MFN1, OPA1), and cell death markers (cleaved caspase-3, NLRP3, LC3-II) were evaluated. Results Compared with APP/PS1 mice without CCH, APP/PS1 mice subjected to CCH exhibited severe cognitive impairment, increased Aβ40 immunoreactivity, enhanced astrocyte reactivity, and altered expression of mitochondrial dynamics-associated proteins, accompanied by elevated levels of apoptosis-associated, inflammasome-associated, and autophagosome-associated markers. NSC trans-plantation markedly improved cognitive performance, reduced Aβ40 immuno-reactivity and astrocyte activation, altered mitochondrial dynamics-associated protein expression, and suppressed cell death-associated protein expression. In contrast, undifferentiated iPSC transplantation showed no significant therapeutic benefit under the conditions tested, potentially reflecting differences in differenti-ation state rather than an intrinsic limitation of iPSC-based therapy. Discussion These findings suggest that NSC transplantation confers neuroprotective effects in AD+CCH, associated with changes in mitochondrial dynamics-associated protein expres-sion and reduced abundance of multiple PCD-associated markers, although the present data do not establish definitive causal relationships. The limited effects observed with undifferentiated iPSCs underscore the importance of cell state in therapeutic applications. This study provides further evidence supporting the investigation of NSC-based strategies for AD with vascular comorbidity.