Abstract
Neurodegenerative diseases such as Alzheimer’s or Parkinson’s are associated with the prion-like propagation and aggregation of toxic proteins. A long standing hypothesis that amyloid-beta drives Alzheimer’s disease has proven the subject of contemporary controversy; leading to new research in both the role of tau protein and its interaction with amyloid-beta. Conversely, recent work in mathematical modeling has demonstrated the relevance of nonlinear reaction-diffusion type equations to capture essential features of the disease. Such approaches have been further simplified, to network-based models, and offer researchers a powerful set of computationally tractable tools with which to investigate neurodegenerative disease dynamics. Here, we propose a novel, coupled network-based model for a two-protein system that includes an enzymatic interaction term alongside a simple model of aggregate transneuronal damage. We apply this theoretical model to test the possible interactions between tau proteins and amyloid-beta and study the resulting coupled behavior between toxic protein clearance and proteopathic phenomenology. Our analysis reveals ways in which amyloid-beta and tau proteins may conspire with each other to enhance the nucleation and propagation of different diseases, thus shedding new light on the importance of protein clearance and protein interaction mechanisms in prion-like models of neurodegenerative disease.
Highlights
Neurodegenerative diseases such as Alzheimer’s (AD) or Parkinson’s (AD) are associated with the propagation and aggregation of toxic proteins
Our model clearly suggests that: the removal rate of toxic protein plays a critical role in AD; and the Aβ-tau ‘conspiracy theory’ is a nuanced, and exciting path forward for Alzheimer’s disease research
In the case of AD, it was Alzheimer himself who showed the importance of both amyloid-β (Aβ) plaques and tau-protein neurofibrillary tangles (NFT) in what he called the “disease of forgetfulness” [1, 2]
Summary
Neurodegenerative diseases such as Alzheimer’s (AD) or Parkinson’s (AD) are associated with the propagation and aggregation of toxic proteins. In the case of AD, it was Alzheimer himself who showed the importance of both amyloid-β (Aβ) plaques and tau-protein (τP) neurofibrillary tangles (NFT) in what he called the “disease of forgetfulness” [1, 2]. Since the early 90’s, when it was first formulated, the “amyloid cascade hypothesis” has dominated the search for cures and treatments [5, 6] According to this hypothesis, an imbalance between production and clearance of Aβ42 and other Aβ peptides is an early indicator of the disease but the causing factor for its initiation, progression, and pathogenesis [7]. The repeated failures of large clinical trials focussing on the reduction of Aβ plaques has led many researchers to question the amyloid hypothesis and argue for the possible importance of other mechanisms
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
