Table 1.
Stem cell transplantation studies on animal models of Alzheimer’s disease.
| Reference | AD model | Stem cell source | Transplantation route | Observation time after transplantation | Molecular change | Cognitive change | Key findings |
|---|---|---|---|---|---|---|---|
| Blurton-Jones et al., 2009 | 3xTg-AD mice, 18-month-old | NSCs from mice with the same haplotype. | Stereotactically delivered to hippocampus. | 1 months | Aβ, tau → BDNF ↑ Hippocampal synaptic density↑ | Spatial learning↑ Novel object recognition↑ | NSCs enhance cognition via BDNF without ameliorating Aβ or tau, as confirmed by loss-of-function study. |
| Lee et al., 2009a | Aβ injection to DG of C57BL/6 mice, | Bone marrow-derived MSCs from mice | Inject to bilateral hippocampus | 7 and 30 days | After 7 days: Microglial activated to reduce Aβ Microglial morphology change After 30 days: No significant difference | NA | Microglial activation after MSC transplantation is involved in ameliorating Aβ. |
| Lee et al., 2009b Lee H.J. et al., 2012 | 2xTg-AD mice, 7 months 1 week old | Bone marrow-derived MSCs | Inject to bilateral hippocampus | 6 weeks | Aβ, tau, β-secretase -1↓ Alternatively activated microglial activation↑ | Spatial memory↑ | Transplantation of MSCs ameliorate Aβ via microglial activation. Microglial phenotype switch from classic to alternative phenotype. |
| Ryu et al., 2009 | Aβ injection to rat hippocampus | NPCs from rat embryos | Stereotactically delivered to hippocampus | 7 days | NPCs tend to migrate to Aβ microgliosis↓ astrogliosis→ TNF-α↓ Attenuate Aβ-induced neuron loss | NA | Transplantation of NPCs attenuate Aβ-induced inflammation. |
| Lee et al., 2010 | Aβ injection to DG of C57BL/6 mice, 12-week-old | Human umbilical cord-derived MSCs | Inject to bilateral hippocampus | 7 days | Apoptosis in hippocampus↓ Oxidative stress↓ Glial activation↓ | Spatial memory↑ | Transplantation reduces Aβ-induced apoptosis in hippocampus. |
| Klinge et al., 2011 | 2xTg-AD mice, 3-month-old | Human bone marrow derived naive MSCs or MSCs transfected with GLP-1 | Stereotactically injected to right ventricle | 2 months | Without GLP-1 transfection: Aβ↓ With GLP-1 transfection: Aβ→ Glial and microglial suppression | NA | Encapsulated MSCs transfected with GLP-1 may cause unexpected microenvironment alteration, mechanism unknown. |
| Kim J.-Y. et al., 2012 | 2xTg-AD mice, 10-month-old | Human umbilical cord-derived MSCs | Inject to bilateral hippocampus, or cisterna magna | 10, 20, and 40 days | Aβ in remote cortices (hypothalamus, amygdale, striatum) ↓ Neprilysin expression in microgli↑a Soluble intracellular adhesion molecule-1 (sICAM-1)↑ | NA | Transplanted MSCs actively migrates to Aβ. sICAM-1 secreted by MSCs induces neprilysin expression in microglia via sICAM-1/LFA-1 pathway. |
| Kim S. et al., 2012 | Tg2576 mice, 11-month-old | Autologous adipose derived stem cell | Intravenously injected or intracerebral injection | 4 months | Aβ, APP↓ VEGF, GDNF, NT3↑ IL-10, anti-inflammatory cytokine↑ Endogenous neurogenesis↑ | Spatial learning↑ | Intravenous administration of adipose derived stem cells are permeable to blood–brain barrier in AD patients, representing a promising preventive strategy for AD. |
| Yang et al., 2013 | 2xTg-AD mice, 6-month-old | Neuron-like cell induced by D609 from human umbilical cord derived MSCs | Stereotactically injected to hippocampus | 3 weeks | Aβ↓ M2-like microglial? Synapsin I↑ M2-like microgli↑a Proinflammatory cytokine↓ Anti-inflammatory cytokine↑ | Spatial learning↑ Spatial memory↑ | Transplantation of neuron-like cells differentiated from mesenchymal stem cell activates M2-like microglia to decrease Aβ and improve memory. |
| Blurton-Jones et al., 2014 | 3xTg-AD mice and Thy1-APP mice | Genetically modified NSCs stably secreting neprilysin. | Stereotactically delivered to subiculum (3xTg-AD mice), hippocampus (Thy1-APP mice). | 3 months | Aβ↓ synaptic density↑ Aβ loads decreased not only in the surrounding area of exogenous NSC transplantation, but also in the projected areas. | NA | Utilizing the migratory NSC to deliver drug. Genetically modified NSC is an effective combinatorial therapy for AD. |
| Garcia et al., 2014 | 2xTg-AD mice, 6-, 9-, and 12-month-old | Bone marrow derived MSCs from mice, transfected with Vascular endothelial growth factor (VEGF) | Stereotactically injected to lateral ventrical | 40 days | Neovascularization in hippocampus Aβ↓ in DG Astrocyte and microglial cell expression↓ | Social recognition memory↑ Interest in novelty↑ | MSC transplantation transfected with VEGF promotes neovascularization even in elder mice. |
| Ager et al., 2015 | CaM/TetDTA mice, 7-month-old or 3xTg-AD mice, 19-month-old | Human NSC from donated fetal brain tissue | Stereotactically injected to hippocampus | 4 weeks | Aβ, tau → Synaptic density↑ | Spatial learning↑ Novel object recognition↑ | Human NSCs migrate and differentiate into neurons and glia, elevate endogenous synaptogenesis. |
| Danielyan et al., 2014 | 2xTg-AD mice, 13-month-old | Bone marrow derived MSCs, macrophages and microglia | Intranasal delivery | 2 weeks | Cells delivered to Olfactory Bulb, hippocampus, cortex and cerebellum. Delivered cells were Aβ positive. | NA | Intranasal stem cell delivery to CNS is a promising alternative route to avoid invasiveness. |
| Kim D.H. et al., 2015 | 2xTg-AD mice | Human umbilical cord blood derived MSCs, GDF-15 recombinant treatment | Repeated cisterna magna injections | 12 weeks | Aβ↓ Synaptic vesicle↑ Endogenous neurogenesis in DG↑ GDF-15↑ | NA | Repeated magna injections of MSCs is more beneficial than single injection. It enhanced neurogenesis and synaptic activity, modulated by paracrine effect of GDF-15. |
| Kim J.A. et al., 2015 | Tg2576 mice 12-months-old and 15- months-old | NSCs from mouse embryo | Stereotactically injected to bilateral DG of hippocampus and the third ventricle | 2 months | 12-months-old: Aβ↓ inflammatory microglia activation↓ Neurogenesis↑ Synapse formation↑ 15- months-old: Aβ→ | 12-months-old: Spatial memory↑ 15-months-old: Spatial memory→ | Early transplantation reduces neuropathology and rescues cognitive decline while transplantation for advanced stage is ineffective. |
| Zhang et al., 2015 | 2xTg-AD mice, 12-month-old | NSCs from mouse embryo. | Stereotactically injected to bilateral ventricles | 5 and 10 weeks | Mitochondrial biogenesis related factors (PGC-1α, NRF-1, and COXIVP)↑ 10 months after transplantation, mtDNA in transplanted 2xTg-AD mice is equivalent to Wt mice. Mitochondrial fission/fusion balance alteration | Spatial learning and memory↑ | NSC transplantation increases mitochondrial biogenesis by modulating the balance between mitochondria fission and fusion. |
| Misra et al., 2016 | Intracerebroventricular -isoproterenol-induced rat | Bone marrow derived MSCs in combination with solid lipid nanoparticle (SLN) encapsulated galantamine hydrobromide (GH) | Intravenous delivery of stem cell, oral delivery of GH-SLNs | 26 days | Antioxidant↑ Neurotrophic factor↑ Anti-apoptotic protein↑ Inflammatory mediators↓ | Spatial memory↑ | SLN encapsulated GH restores antioxidant levels in brain, enhancing the efficacy of stem cell treatment. |
| Wu et al., 2016 | Tg 2576 mice, 16-month-old | BDNF overexpressing NSCs derived from mice | Stereotactically injected to hippocampus | 2, 4, and 8 weeks | BDNF overexpression increases viability and neuronal fate of engrafted NSCs. Hippocampal BDNF and synaptic density↑ | Spatial memory↑ Novel object recognition↑ | Transplanting genetically altered NSCs is a promising strategy. |
↑ stands for elevated levels were observed.
↓ stands for decreased levels were observed.
→ stands for no significant change of levels were observed.
NA stands for not analyzed.
2xTg-AD mice express APP and PS1 mutation.
3xTg-AD mice express APP, PS1 and MAPT mutation.
5XFAD mice overexpress 3 APP mutations and 2 PS1 mutations.
CaM/TetDTA is a mouse model characterized by loss of hippocampal CA1 neurons.