A kinetic model predicts that tau-catalyzed Aβ nucleation can raise oligomer burden without increasing plaque volume
Abstract
Tau and amyloid-β (Aβ) deposits co-occur in Alzheimer's disease, and tau fibrils have recently been shown in vitro to catalyze Aβ primary nucleation in a fold-specific manner. A two-compartment kinetic model is developed here, describing tau aggregation within the neuronal soma and Aβ aggregation in the surrounding interstitium. The adjustable coupling parameter is the fraction facc of somatic tau fibrillar material accessible to interstitial Aβ. Homotypic Aβ secondary nucleation is restricted to the accessible surface of the consolidating plaque rather than scaling with total fibril mass, which preserves the in vitro calibration of the rate constant while preventing the surface term from growing without bound over decades. Three model predictions emerge. First, the model predicts that tau-catalyzed nucleation can increase the soluble Aβ oligomer concentration and the number of Aβ fibrillar species, by factors of 4.6 and 2.0, respectively, at complete accessibility, while leaving total Aβ fibril mass and plaque volume unchanged, since in the absence of clearance these are fixed by the monomer supply; oligomer burden and visible plaque burden are therefore decoupled. Second, the predicted effect requires substantial accessibility: a 50 % increase in accumulated oligomer exposure needs facc ≈ 0.035-0.15, which is difficult to reconcile with tangles enclosed by an intact neuronal membrane and points instead to neuronal lysis and the formation of extracellular ghost tangles. Third, physiologically relevant oligomer dissociation and proteolytic turnover each suppress accumulated exposure, by approximately three orders of magnitude and, at zero tau accessibility, about seventyfold, respectively, and remove the effect on a biological-age measure entirely.
Related
- Embedding response surfaces in kinetic models predicts microalgae growth across light and nutrient gradients
- Tau Disaggregation by a CNS-Permeable Small Molecule Reduces Fibril and Oligomer Burden and Preserves Proteostasis and Behavior
- Apolipoprotein E4 Exacerbates Aβ Oligomer-Induced Synaptotoxicity through Promoting Autophagic Degradation of Glutathione Peroxidase 4
- Toward Increasing Cost‐Effectiveness of Genetic Testing in Movement Disorders
- Health prevention research in France: Increasing investment is a priority, rethinking targets is equally crucial
BibTeX
@misc{kuznetsov2026kinetic,
title = {{A kinetic model predicts that tau-catalyzed A$β$ nucleation can raise oligomer burden without increasing plaque volume}},
author = {Andrey V. Kuznetsov},
howpublished = {arXiv},
year = {2026},
month = sep,
doi = {10.48550/arxiv.2609.38708},
eprint = {2609.38708},
archivePrefix = {arXiv},
url = {https://arxiv.org/abs/2609.38708},
}
RIS
TY - UNPB
TI - A kinetic model predicts that tau-catalyzed Aβ nucleation can raise oligomer burden without increasing plaque volume
AU - Andrey V. Kuznetsov
PY - 2026
DA - 2026/09/30
PB - arXiv
DO - 10.48550/arxiv.2609.38708
UR - https://arxiv.org/abs/2609.38708
AB - Tau and amyloid-β (Aβ) deposits co-occur in Alzheimer's disease, and tau fibrils have recently been shown in vitro to catalyze Aβ primary nucleation in a fold-specific manner. A two-compartment kinetic model is developed here, describing tau aggregation within the neuronal soma and Aβ aggregation in the surrounding interstitium. The adjustable coupling parameter is the fraction f_acc of somatic tau fibrillar material accessible to interstitial Aβ. Homotypic Aβ secondary nucleation is restricted to the accessible surface of the consolidating plaque rather than scaling with total fibril mass, which preserves the in vitro calibration of the rate constant while preventing the surface term from growing without bound over decades. Three model predictions emerge. First, the model predicts that tau-catalyzed nucleation can increase the soluble Aβ oligomer concentration and the number of Aβ fibrillar species, by factors of 4.6 and 2.0, respectively, at complete accessibility, while leaving total Aβ fibril mass and plaque volume unchanged, since in the absence of clearance these are fixed by the monomer supply; oligomer burden and visible plaque burden are therefore decoupled. Second, the predicted effect requires substantial accessibility: a 50 % increase in accumulated oligomer exposure needs f_acc ≈ 0.035-0.15, which is difficult to reconcile with tangles enclosed by an intact neuronal membrane and points instead to neuronal lysis and the formation of extracellular ghost tangles. Third, physiologically relevant oligomer dissociation and proteolytic turnover each suppress accumulated exposure, by approximately three orders of magnitude and, at zero tau accessibility, about seventyfold, respectively, and remove the effect on a biological-age measure entirely.
ER -