A New Bistable Switch Model of Alzheimer’s Disease Pathogenesis
We propose a model to explain the pathogenesis of Alzheimer’s disease (AD) based on the theory that any disease affecting a healthy organism originates from a bistable feedback loop that shifts the system from a physiological to a pathological condition. We focused on the known double inhibitory loo...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/13/7061 |
| _version_ | 1797479817266855936 |
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| author | Bruno Burlando Serena Losacco Viviana Villa Ernesto Fedele Roberta Ricciarelli |
| author_facet | Bruno Burlando Serena Losacco Viviana Villa Ernesto Fedele Roberta Ricciarelli |
| author_sort | Bruno Burlando |
| collection | DOAJ |
| description | We propose a model to explain the pathogenesis of Alzheimer’s disease (AD) based on the theory that any disease affecting a healthy organism originates from a bistable feedback loop that shifts the system from a physiological to a pathological condition. We focused on the known double inhibitory loop involving the cellular prion protein (PrPC) and the enzyme BACE1 that produces amyloid-beta (Aβ) peptides. BACE1 is inhibited by PrPC, but its inhibitory activity is lost when PrPC binds to Aβ oligomers (Aβo). Excessive Aβo formation would switch the loop to a pathogenic condition involving the Aβo-PrPC-mGluR5 complex, Fyn kinase activation, tau, and NMDAR phosphorylation, ultimately leading to neurodegeneration. Based on the emerging role of cyclic nucleotides in Aβ production, and thereby in synaptic plasticity and cognitive processes, cAMP and cGMP can be considered as modulatory factors capable of inducing the transition from a physiological steady state to a pathogenic one. This would imply that critical pharmacological targets for AD treatment lie within pathways that lead to an imbalance of cyclic nucleotides in neurons. If this hypothesis is confirmed, it will provide precise indications for the development of preventive or therapeutic treatments for the disease. |
| first_indexed | 2024-03-09T21:51:15Z |
| format | Article |
| id | doaj.art-cbe19c9692354654ae987afc60732ac0 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T21:51:15Z |
| publishDate | 2022-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-cbe19c9692354654ae987afc60732ac02023-11-23T20:07:40ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-06-012313706110.3390/ijms23137061A New Bistable Switch Model of Alzheimer’s Disease PathogenesisBruno Burlando0Serena Losacco1Viviana Villa2Ernesto Fedele3Roberta Ricciarelli4Department of Pharmacy (DIFAR), University of Genoa, 16132 Genoa, ItalyDepartment of Pharmacy (DIFAR), University of Genoa, 16132 Genoa, ItalyDepartment of Experimental Medicine (DIMES), University of Genoa, 16132 Genoa, ItalyDepartment of Pharmacy (DIFAR), University of Genoa, 16132 Genoa, ItalyDepartment of Experimental Medicine (DIMES), University of Genoa, 16132 Genoa, ItalyWe propose a model to explain the pathogenesis of Alzheimer’s disease (AD) based on the theory that any disease affecting a healthy organism originates from a bistable feedback loop that shifts the system from a physiological to a pathological condition. We focused on the known double inhibitory loop involving the cellular prion protein (PrPC) and the enzyme BACE1 that produces amyloid-beta (Aβ) peptides. BACE1 is inhibited by PrPC, but its inhibitory activity is lost when PrPC binds to Aβ oligomers (Aβo). Excessive Aβo formation would switch the loop to a pathogenic condition involving the Aβo-PrPC-mGluR5 complex, Fyn kinase activation, tau, and NMDAR phosphorylation, ultimately leading to neurodegeneration. Based on the emerging role of cyclic nucleotides in Aβ production, and thereby in synaptic plasticity and cognitive processes, cAMP and cGMP can be considered as modulatory factors capable of inducing the transition from a physiological steady state to a pathogenic one. This would imply that critical pharmacological targets for AD treatment lie within pathways that lead to an imbalance of cyclic nucleotides in neurons. If this hypothesis is confirmed, it will provide precise indications for the development of preventive or therapeutic treatments for the disease.https://www.mdpi.com/1422-0067/23/13/7061amyloid-βBACE1cellular prion proteincyclic nucleotidesbistable switchfeedback loop |
| spellingShingle | Bruno Burlando Serena Losacco Viviana Villa Ernesto Fedele Roberta Ricciarelli A New Bistable Switch Model of Alzheimer’s Disease Pathogenesis International Journal of Molecular Sciences amyloid-β BACE1 cellular prion protein cyclic nucleotides bistable switch feedback loop |
| title | A New Bistable Switch Model of Alzheimer’s Disease Pathogenesis |
| title_full | A New Bistable Switch Model of Alzheimer’s Disease Pathogenesis |
| title_fullStr | A New Bistable Switch Model of Alzheimer’s Disease Pathogenesis |
| title_full_unstemmed | A New Bistable Switch Model of Alzheimer’s Disease Pathogenesis |
| title_short | A New Bistable Switch Model of Alzheimer’s Disease Pathogenesis |
| title_sort | new bistable switch model of alzheimer s disease pathogenesis |
| topic | amyloid-β BACE1 cellular prion protein cyclic nucleotides bistable switch feedback loop |
| url | https://www.mdpi.com/1422-0067/23/13/7061 |
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