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Endosomal pH Triggers Amyloid β Oligomerization and Maladaptive Phenotypic Plasticity in Alzheimers Disease
Meena RK, Duddu AS, Jolly MK, Prasad H.. bioRxiv, 2026-09-28
Topic: Disease mechanisms in lab and animal studies
Endosomal dysfunction is a presymptomatic hallmark of neurodegeneration. Recent evidence highlights dysregulation of endosomal pH as a central pathogenic hub in Alzheimer's disease (AD); however, the mechanisms linking pH shifts to neurodegeneration remain incompletely defined. Here, we use a quantitative model of endosomal acidification driven by proton pumping via the vacuolar ATPase, proton leak via the endosomal Na⁺/H⁺ exchanger NHE6, and other ion-regulating elements. The model recapitulates how downregulation of NHE6 in AD promotes endosomal hyperacidification, potentially triggering maladaptive phenotypic plasticity, an initially adaptive response that becomes pathological. Analysis of human brain datasets reveals reciprocal enrichment of NHE6 in neurons and the related NHE9 in glia, with NHE6 co-expression networks enriched for synaptic signalling. Systematic curation of NHE6 patient variants indicates that loss-of-function is associated with late regression, consistent with progressive endosomal hyperacidification, supporting a conceptual framework where early compensation transitions to neurodegeneration. Mathematical analyses calibrated for neuronal endosomes reveal a saturable relationship between luminal pH and NHE6 dosage, with threshold-like behaviour below ~50% expression that hyperacidifies endosomes, correlating with AD severity. Our model suggests this pH shift may exponentially accelerate Aβ oligomerization and enhance β-secretase activity. Furthermore, Aβ oligomerization estimates correlate with dysregulation of calcium signalling and synaptic dysfunction. Model findings are compared with experimental results from NHE6-null mice and a cell culture model of AD. Drawing parallels to cancer, we propose that endosomal pH serves as a conserved regulator of adaptive-to-maladaptive transitions. Restoring physiological endosomal pH may offer a therapeutic window to prevent irreversible neurodegeneration in AD.
Key findings
- Systematic curation of NHE6 patient variants indicates that loss-of-function is associated with late regression, consistent with progressive endosomal hyperacidification, supporting a conceptual framework where early compensation transitions to neurodegeneration.
- Model findings are compared with experimental results from NHE6-null mice and a cell culture model of AD.
Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 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 13 of the 62 points we could judge it on, which is 21 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 | 5 / 5 | 2026 — within 1 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 | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 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
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APA 7th
Meena, R. K., Duddu, A. S., Jolly, M. K., & Prasad, H. (2026). Endosomal pH Triggers Amyloid β Oligomerization and Maladaptive Phenotypic Plasticity in Alzheimers Disease. bioRxiv. https://doi.org/10.64898/2026.09.23.752284
Vancouver
Meena RK, Duddu AS, Jolly MK, Prasad H. Endosomal pH Triggers Amyloid β Oligomerization and Maladaptive Phenotypic Plasticity in Alzheimers Disease. bioRxiv. 2026. doi:10.64898/2026.09.23.752284.
BibTeX
@article{meena2026-5c2dbb27,
author = {Meena, R. K. and Duddu, A. S. and Jolly, M. K. and Prasad, H.},
title = {{Endosomal pH Triggers Amyloid β Oligomerization and Maladaptive Phenotypic Plasticity in Alzheimers Disease}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.09.23.752284},
url = {https://doi.org/10.64898/2026.09.23.752284}
}
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