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Alzheimer’s disease (AD) is characterized by distinct tissue changes associated with accumulation of extracellular amyloid-beta (Aβ) peptides, and intracellular deposits of phosphorylated Tau (p-tau). There is a clear need to develop 3D AD model for alternative to animal test since current rodent model does not recapitulate complex human AD physiopathology. Here we report on organoid-grafted neurovascular unit (NUV) using 1) spheroid using APP-mutated neuro-progenitor cell and 2) endothelial-based blood brain barrier (BBB) against extracellular matrix. The construct was validated with AD pathology generation and further treatment with β- or γ-secretase inhibitors shows the decrease of Aβ. This paper demonstrates the potential utility of a membrane-free in vitro cortical spheroid tissue construct with BBB in a high throughput platform to model AD.
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This content will become publicly available on April 1, 2026
Modelling cerebrovascular pathology and the spread of amyloid beta in Alzheimer’s disease
Alzheimer’s disease (AD) is characterized in part by the accumulation and spread of amyloid beta proteins in the brain. Recent experiments have revealed that amyloid beta oligomers induce microvascular mural cells to contract, thereby constricting capillaries and increasing resistance to blood flow. Conversely, hypoperfusion promotes amyloid beta production and hinders its clearance, hence creating a pathogenic positive feedback loop. Here, we develop a mathematical model that combines protein–capillary interaction with the prion-like behaviour of amyloid beta. For sufficiently strong interaction, we find that healthy and diseased steady states, both stable, can exist simultaneously, implying that pathogenic protein seeds must exceed a critical threshold in order to trigger disease outbreak. We explore the consequences of this bistability for disease propagation through the brain’s structural connectome network. Finally, in a first attempt to model the AD two-hit vascular hypothesis mathematically, we describe how spatially localized deficits in blood supply, e.g. due to embolic stroke or atherosclerosis of the leptomeningeal vessels, may trigger disease outbreak and propagation.
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- Award ID(s):
- 2325276
- PAR ID:
- 10620604
- Publisher / Repository:
- The Royal Society
- Date Published:
- Journal Name:
- Proceedings of the Royal Society A: Mathematical, Physical and Engineering Sciences
- Volume:
- 481
- Issue:
- 2311
- ISSN:
- 1364-5021
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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