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Neural stem cells genetically-modified to express neprilysin reduce pathology in Alzheimer transgenic models
Blurton-Jones M, Spencer B, Michael S, Castello NA, Agazaryan AA, Davis JL, Müller FJ, Loring JF et al.. Stem cell research & therapy, 2014-04-16
Topic: Brain proteins, microglia and lab models
Introduction Short-term neural stem cell (NSC) transplantation improves cognition in Alzheimer's disease (AD) transgenic mice by enhancing endogenous synaptic connectivity. However, this approach has no effect on the underlying beta-amyloid (Aβ) and neurofibrillary tangle pathology. Long term efficacy of cell based approaches may therefore require combinatorial approaches. Methods To begin to examine this question we genetically-modified NSCs to stably express and secrete the Aβ-degrading enzyme, neprilysin (sNEP). Next, we studied the effects of sNEP expression in vitro by quantifying Aβ-degrading activity, NSC multipotency markers, and Aβ-induced toxicity. To determine whether sNEP-expressing NSCs can also modulate AD-pathogenesis in vivo, control-modified and sNEP-NSCs were transplanted unilaterally into the hippocampus of two independent and well characterized transgenic models of AD: 3xTg-AD and Thy1-APP mice. After three months, stem cell engraftment, neprilysin expression, and AD pathology were examined. Results Our findings reveal that stem cell-mediated delivery of NEP provides marked and significant reductions in Aβ pathology and increases synaptic density in both 3xTg-AD and Thy1-APP transgenic mice. Remarkably, Aβ plaque loads are reduced not only in the hippocampus and subiculum adjacent to engrafted NSCs, but also within the amygdala and medial septum, areas that receive afferent projections from the engrafted region. Conclusions Taken together, our data suggest that genetically-modified NSCs could provide a powerful combinatorial approach to not only enhance synaptic plasticity but to also target and modify underlying Alzheimer's disease pathology.
Key findings
- Results Our findings reveal that stem cell-mediated delivery of NEP provides marked and significant reductions in Aβ pathology and increases synaptic density in both 3xTg-AD and Thy1-APP transgenic mice.
- Conclusions Taken together, our data suggest that genetically-modified NSCs could provide a powerful combinatorial approach to not only enhance synaptic plasticity but to also target and modify underlying Alzheimer's disease pathology.
Why it matters
In two mouse models of Alzheimer's disease, transplanted neural stem cells engineered to release an amyloid-degrading enzyme reduced amyloid plaques and increased synaptic density. These are animal results only, and it is not known whether this approach would be safe or effective in people.
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Study details
- Evidence strengthLow
How this study scored 46/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Stem cell research & therapy) |
| Journal's citation record | 2 / 4 | Stem Cell Research & Therapy: journal h-index 176 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2014 — within 20 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Laboratory or animal study (title names “transgenic”) — scores zero |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 5 / 7 | Cited 116 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 8.3 citations a year over 14 year(s) since 2014 |
| Impact for its field and year | 4 / 6 | Cited 9.9× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 11 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Frank M. LaFerla: h-index 114 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of California San Diego: institution h-index 1,852 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 4 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 25022790) |
| Free to read | 2 / 2 | Free to read |
| Total | 46 / 100 | — |
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Read the original
- DOI: 10.1186/scrt440
- PubMed: 25022790
- Original source →
- Free full text: Stem Cell Research & Therapy →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Blurton-Jones, M., Spencer, B., Michael, S., Castello, N. A., Agazaryan, A. A., Davis, J. L., et al. (2014). Neural stem cells genetically-modified to express neprilysin reduce pathology in Alzheimer transgenic models. Stem cell research & therapy. https://doi.org/10.1186/scrt440
Vancouver
Blurton-Jones M, Spencer B, Michael S, Castello NA, Agazaryan AA, Davis JL, et al. Neural stem cells genetically-modified to express neprilysin reduce pathology in Alzheimer transgenic models. Stem cell research & therapy. 2014. doi:10.1186/scrt440. PMID: 25022790.
BibTeX
@article{blurtonjones2014-25022790,
author = {Blurton-Jones, M. and Spencer, B. and Michael, S. and Castello, N. A. and Agazaryan, A. A. and Davis, J. L. and Müller, F. J. and Loring, J. F. and others},
title = {{Neural stem cells genetically-modified to express neprilysin reduce pathology in Alzheimer transgenic models}},
journal = {Stem cell research \& therapy},
year = {2014},
doi = {10.1186/scrt440},
pmid = {25022790},
url = {https://doi.org/10.1186/scrt440}
}
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