Restricted accessResearch articleFirst published online 2025
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.
KuruvaCSReddyPH.Amyloid beta modulators and neuroprotection in Alzheimer’s disease: a critical appraisal. Drug Discov Today2017; 22(2): 223–233.
2.
MekalaAQiuH.Interplay between vascular dysfunction and neurodegenerative pathology: new insights into molecular mechanisms and management. Biomolecules2025; 15(5): 712.
3.
EisenmengerLBPeretAFamakinBM, et al. Vascular contributions to Alzheimer’s disease. Transl Res2023; 254: 41–53.
4.
Di MarcoLYVenneriAFarkasE, et al. Vascular dysfunction in the pathogenesis of Alzheimer’s disease—a review of endothelium-mediated mechanisms and ensuing vicious circles. Neurobiol Dis2015; 82: 593–606.
ShangJYamashitaTZhaiY, et al. Strong impact of chronic cerebral hypoperfusion on neurovascular unit, cerebrovascular remodeling, and neurovascular trophic coupling in Alzheimer’s disease model mouse. J Alzheimers Dis2016; 52(1): 113–126.
7.
QiuZZhangHXiaM, et al. Programmed death of microglia in Alzheimer’s disease: autophagy, ferroptosis, and pyroptosis. J Prev Alzheimers Dis2023; 10(1): 95–103.
8.
YangQYangCLvH, et al. Autophagy regulation attenuates neuroinflammation and cognitive decline in an Alzheimer’s disease mouse model with chronic cerebral hypoperfusion. Inflammation2025; 48(2): 541–556.
9.
JiangDLiuHLiT, et al. Agomirs upregulating carboxypeptidase E expression rescue hippocampal neurogenesis and memory deficits in Alzheimer’s disease. Transl Neurodegener2024; 13(1): 24.
10.
MitsialisSAKourembanasS.Stem cell-based therapies for the newborn lung and brain: possibilities and challenges. Semin Perinatol2016; 40(3): 138–151.
11.
OhBSwaminathanVMalkovskiyA, et al. Single-cell encapsulation via click-chemistry alters production of paracrine factors from neural progenitor cells. Adv Sci2020; 7(8): 1902573.
12.
IoannidouE.Therapeutic modulation of growth factors and cytokines in regenerative medicine. Curr Pharm Des2006; 12(19): 2397–2408.
13.
GögelSGubernatorMMingerSL.Progress and prospects: stem cells and neurological diseases. Gene Ther2011; 18(1): 1–6.
14.
FengZGaoF.Stem cell challenges in the treatment of neurodegenerative disease. CNS Neurosci Ther2012; 18(2): 142–148.
15.
LuoMZengQJiangK, et al. Estrogen deficiency exacerbates learning and memory deficits associated with glucose metabolism disorder in APP/PS1 double transgenic female mice. Genes Dis2022; 9(5): 1315–1331.
16.
AsoELomoioSLópez-GonzálezI, et al. Amyloid generation and dysfunctional immunoproteasome activation with disease progression in animal model of familial Alzheimer’s disease. Brain Pathol2012; 22(5): 636–653.
17.
Bilkei-GorzoA.Genetic mouse models of brain ageing and Alzheimer’s disease. Pharmacol Ther2014; 142(2): 244–257.
18.
ShangJYamashitaTZhaiY, et al. Acceleration of NLRP3 inflammasome by chronic cerebral hypoperfusion in Alzheimer’s disease model mouse. Neurosci Res2019; 143: 61–70.
19.
ShangJYamashitaTTianF, et al. Chronic cerebral hypoperfusion alters amyloid-β transport related proteins in the cortical blood vessels of Alzheimer’s disease model mouse. Brain Res2019; 1723: 146379.
20.
ZhaoBYangDJiangJ, et al. Genome-wide mapping of miRNAs expressed in embryonic stem cells and pluripotent stem cells generated by different reprogramming strategies. BMC Genomics2014; 15(1): 488.
21.
WangLDuYWangK, et al. Chronic cerebral hypoperfusion induces memory deficits and facilitates Aβ generation in C57BL/6J mice. Exp Neurol2016; 283(Pt A): 353–364.
22.
KokjohnTAMaaroufCLRoherAE.Is Alzheimer’s disease amyloidosis the result of a repair mechanism gone astray?Alzheimers Dement2012; 8(6): 574–583.
23.
YangQChenTLiS, et al. Inhibition of autophagy attenuates cognitive decline and mitochondrial dysfunction in an Alzheimer’s disease mouse model with chronic cerebral hypoperfusion. Brain Res2025; 1850: 149416.
24.
LanaDMelaniAPuglieseAM, et al. The neuron-astrocyte-microglia triad in a rat model of chronic cerebral hypoperfusion: protective effect of dipyridamole. Front Aging Neurosci2014; 6: 322.
25.
JearjaroenPThangwongPTocharusC, et al. Hexahydrocurcumin attenuates neuronal injury and modulates synaptic plasticity in chronic cerebral hypoperfusion in rats. Mol Neurobiol2024; 61(7): 4304–4317.
26.
GovindpaniKMcNamaraLGSmithNR, et al. Vascular dysfunction in Alzheimer’s disease: a prelude to the pathological process or a consequence of it?J Clin Med2019; 8(5): 651.
27.
WeiKWangPMiaoCY.A double-edged sword with therapeutic potential: an updated role of autophagy in ischemic cerebral injury. CNS Neurosci Ther2012; 18(11): 879–886.
28.
ShiCSShenderovKHuangNN, et al. Activation of autophagy by inflammatory signals limits IL-1β production by targeting ubiquitinated inflammasomes for destruction. Nat Immunol2012; 13(3): 255–263.
29.
SongYDuYZouW, et al. Involvement of impaired autophagy and mitophagy in Neuro-2a cell damage under hypoxic and/or high-glucose conditions. Sci Rep2018; 8(1): 3301.
30.
DaulatzaiMA.Cerebral hypoperfusion and glucose hypometabolism: key pathophysiological modulators promote neurodegeneration, cognitive impairment, and Alzheimer’s disease. J Neurosci Res2017; 95(4): 943–972.
31.
GheniGShinoharaMMasuda-SuzukakeM, et al. Cerebral hypoperfusion reduces tau accumulation. Ann Clin Transl Neurol2025; 12(1): 69–85.
32.
YuMZhengXChengF, et al. Metformin, rapamycin, or nicotinamide mononucleotide pretreatment attenuate cognitive impairment after cerebral hypoperfusion by inhibiting microglial phagocytosis. Front Neurol2022; 13: 903565.
33.
SalminenA.Hypoperfusion is a potential inducer of immunosuppressive network in Alzheimer’s disease. Neurochem Int2021; 142: 104919.
34.
WangLWangRChenZ, et al. Xinnao Shutong modulates the neuronal plasticity through regulation of microglia/macrophage polarization following chronic cerebral hypoperfusion in rats. Front Physiol2018; 9: 529.
35.
YangJWiseLFukuchiKI.TLR4 cross-talk with NLRP3 inflammasome and complement signaling pathways in Alzheimer’s disease. Front Immunol2020; 11: 724.
36.
CuiWSunCMaY, et al. Inhibition of TLR4 induces M2 microglial polarization and provides neuroprotection via the NLRP3 inflammasome in Alzheimer’s disease. Front Neurosci2020; 14: 444.
37.
PerezJLCarreroIGonzaloP, et al. Soluble oligomeric forms of beta-amyloid (Abeta) peptide stimulate Abeta production via astrogliosis in the rat brain. Exp Neurol2010; 223(2): 410–421.
38.
FerrerI.Diversity of astroglial responses across human neurodegenerative disorders and brain aging. Brain Pathol2017; 27(5): 645–674.
39.
QinLCrewsFT.NADPH oxidase and reactive oxygen species contribute to alcohol-induced microglial activation and neurodegeneration. J Neuroinflammation2012; 9: 5.
40.
CuiGHShaoSJYangJJ, et al. Designer self-assemble peptides maximize the therapeutic benefits of neural stem cell transplantation for Alzheimer’s disease via enhancing neuron differentiation and paracrine action. Mol Neurobiol2016; 53(2): 1108–1123.
41.
WangJXiaJZhangF, et al. Galectin-1-secreting neural stem cells elicit long-term neuroprotection against ischemic brain injury. Sci Rep2015; 5: 9621.
42.
WuCCLienCCHouWH, et al. Gain of BDNF function in engrafted neural stem cells promotes the therapeutic potential for Alzheimer’s disease. Sci Rep2016; 6: 27358.
43.
WilliamsGGattAClarkeE, et al. Drug repurposing for Alzheimer’s disease based on transcriptional profiling of human iPSC-derived cortical neurons. Transl Psychiatry2019; 9(1): 220.
44.
HongSGWinklerTWuC, et al. Path to the clinic: assessment of iPSC-based cell therapies in vivo in a nonhuman primate model. Cell Rep2014; 7(4): 1298–1309.
45.
JiangXCXiangJJWuHH, et al. Neural stem cells transfected with reactive oxygen species-responsive polyplexes for effective treatment of ischemic stroke. Adv Mater2019; 31(10): e1807591.
46.
GonzalezRHamblinMHLeeJP.Neural stem cell transplantation and CNS diseases. CNS Neurol Disord Drug Targets2016; 15(8): 881–886.
47.
VaySUFlitschLJRabensteinM, et al. The plasticity of primary microglia and their multifaceted effects on endogenous neural stem cells in vitro and in vivo. J Neuroinflammation2018; 15(1): 226.
48.
YaoXQJiaoSSSaadipourK, et al. p75NTR ectodomain is a physiological neuroprotective molecule against amyloid-beta toxicity in the brain of Alzheimer’s disease. Mol Psychiatry2015; 20(11): 1301–1310.
49.
WuZChenCKangSS, et al. Neurotrophic signaling deficiency exacerbates environmental risks for Alzheimer’s disease pathogenesis. Proc Natl Acad Sci U S A2021; 118(25): e2100986118.
50.
YamadaKMizunoMNabeshimaT.Role for brain-derived neurotrophic factor in learning and memory. Life Sci2002; 70(7): 735–744.
51.
DooleyDVidalPHendrixS.Immunopharmacological intervention for successful neural stem cell therapy: new perspectives in CNS neurogenesis and repair. Pharmacol Ther2014; 141(1): 21–31.
52.
ChengAHouYMattsonMP.Mitochondria and neuroplasticity. ASN Neuro2010; 2(5): e00045.
53.
RudnitskayaEAKolosovaNGStefanovaNA.Impact of changes in neurotrophic supplementation on development of Alzheimer’s disease-like pathology in OXYS rats. Biochemistry2017; 82(3): 318–329.
54.
KimDKyungJParkD, et al. Health span-extending activity of human amniotic membrane- and adipose tissue-derived stem cells in F344 rats. Stem Cells Transl Med2015; 4(10): 1144–1154.
55.
ParkDChoiEKChoTH, et al. Human neural stem cells encoding ChAT gene restore cognitive function via acetylcholine synthesis, Aβ elimination, and neuroregeneration in APPswe/PS1dE9 mice. Int J Mol Sci2020; 21(11): 3958.
56.
KimJShinKChaY, et al. Neuroprotective effects of human neural stem cells over-expressing choline acetyltransferase in a middle cerebral artery occlusion model. J Chem Neuroanat2020; 103: 101730.
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