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Amyloid precursor protein dosage normalization rescues neurogenesis and Alzheimer’s Disease phenotypes associated with Down Syndrome
Patel D, Rakowiecki K, Lazarov O.. bioRxiv, 2025-07-30
Topic: Disease mechanisms in lab and animal studies
Down Syndrome (DS) is the most abundant genetic form of mental retardation. It is caused by the triplication of partial or complete human chromosome 21 (HSA21). The molecular mechanisms causing it are not fully understood. Previous studies identified “Down syndrome Critical Region” (DSCR) genes that are essential or sufficient for the development of DS. However, these studies are largely inconclusive, due, in part, to the reliance on a small number of epidemiological cases. Amyloid precursor protein ( APP ) resides on HSA21 and is triplicated in DS. APP plays a role in developmental and post-natal neurogenesis, but is not thought to be part of the DSCR. The role of APP overdose in cortical malformation and cognitive impairments in DS is unknown. Mutations in APP cause familial Alzheimer’s disease (FAD). However, whether APP overdose is sufficient for the development of Alzheimer’s disease (AD) in DS is not fully understood. Here, we addressed the role of APP overdose in neuronal development and AD pathology. Using CRISPR/Cas9 gene editing, we eliminated one copy of APP from Down Syndrome-derived induced iPSCs DS APP(+/+/-) and examined the effect on neurogenesis, AD-related pathology and the expression levels of genes on HSA21 that are implicated in DS, neurodegeneration and inflammation.
Key findings
- The role of APP overdose in cortical malformation and cognitive impairments in DS is unknown.
- Mutations in APP cause familial Alzheimer’s disease (FAD).
- However, whether APP overdose is sufficient for the development of Alzheimer’s disease (AD) in DS is not fully understood.
- Here, we addressed the role of APP overdose in neuronal development and AD pathology.
- Using CRISPR/Cas9 gene editing, we eliminated one copy of APP from Down Syndrome-derived induced iPSCs DS APP(+/+/-) and examined the effect on neurogenesis, AD-related pathology and the expression levels of genes on HSA21 that are implicated in DS, neurodegeneration and inflammation.
Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 19 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 12 of the 62 points we could judge it on, which is 19 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (bioRxiv) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| 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 | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 4 / 5 | 2025 — within 3 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 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 12 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 12 of the 62 points we could judge it on is 19 out of 100. |
| Total | 19 / 100 | Capped to 16 because this is not a peer-reviewed article. |
What each of these 20 components measures, and what this score is not →
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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. Check the citation against the original before you use it.
APA 7th
Patel, D., Rakowiecki, K., & Lazarov, O. (2025). Amyloid precursor protein dosage normalization rescues neurogenesis and Alzheimer’s Disease phenotypes associated with Down Syndrome. bioRxiv. https://doi.org/10.1101/2025.07.30.667706
Vancouver
Patel D, Rakowiecki K, Lazarov O. Amyloid precursor protein dosage normalization rescues neurogenesis and Alzheimer’s Disease phenotypes associated with Down Syndrome. bioRxiv. 2025. doi:10.1101/2025.07.30.667706.
BibTeX
@article{patel2025-c5fbe4fa,
author = {Patel, D. and Rakowiecki, K. and Lazarov, O.},
title = {{Amyloid precursor protein dosage normalization rescues neurogenesis and Alzheimer’s Disease phenotypes associated with Down Syndrome}},
journal = {bioRxiv},
year = {2025},
doi = {10.1101/2025.07.30.667706},
url = {https://doi.org/10.1101/2025.07.30.667706}
}
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