Alzheimer’s Disease: A Molecular Model and Implied Path to Improved Therapy
Amyloid-associated neurodegenerative diseases, including Alzheimer’s disease (AD), are characterized by the in-brain accumulation of β-sheet structured protein aggregates called amyloids. However, neither a disease model nor therapy is established. We review past data and present new, preliminary da...
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-03-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/25/6/3479 |
| _version_ | 1797240704756350976 |
|---|---|
| author | Meagan Susanne Weaver-Rosen Philip Serwer |
| author_facet | Meagan Susanne Weaver-Rosen Philip Serwer |
| author_sort | Meagan Susanne Weaver-Rosen |
| collection | DOAJ |
| description | Amyloid-associated neurodegenerative diseases, including Alzheimer’s disease (AD), are characterized by the in-brain accumulation of β-sheet structured protein aggregates called amyloids. However, neither a disease model nor therapy is established. We review past data and present new, preliminary data and opinions to help solve this problem. The following is the data-derived model/hypothesis. (1) Amyloid-forming proteins have innate immunity functions implemented by conversion to another sheet conformation, α-sheet. (2) In health, α-sheet structured, amyloid-forming proteins inactivate microbes by co-assembly with microbe α-sheets. Amyloid-forming proteins then undergo α-to-β-sheet conversion. (3) In disease, α-sheet-structured, amyloid-forming proteins over-accumulate and are neuron-toxic. This hypothesis includes formation by virus capsid subunits of α-sheets. In support, we find that 5–10 mM methylene blue (MB) at 54 °C has a hyper-expanding, thinning effect on the phage T4 capsid, as seen by negative stain- and cryo-electron microscopy after initial detection by native gel electrophoresis (AGE). Given the reported mild anti-AD effect of MB, we propose the following corollary hypothesis. (1) Anti-AD MB activity is, at least in part, caused by MB-binding to amyloid α-sheet and (2) MB induces the transition to α-sheet of T4 capsid subunits. We propose using AGE of drug incubated T4 to test for improved anti-AD activity. |
| first_indexed | 2024-04-24T18:11:40Z |
| format | Article |
| id | doaj.art-b50e0274c90b4b82bae1eb7a0af37ad8 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-04-24T18:11:40Z |
| publishDate | 2024-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-b50e0274c90b4b82bae1eb7a0af37ad82024-03-27T13:46:14ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-03-01256347910.3390/ijms25063479Alzheimer’s Disease: A Molecular Model and Implied Path to Improved TherapyMeagan Susanne Weaver-Rosen0Philip Serwer1Department of Microbiology, Immunology and Molecular Genetics, UT Health, San Antonio, TX 78229, USADepartment of Biochemistry and Structural Biology, UT Health, San Antonio, TX 78229, USAAmyloid-associated neurodegenerative diseases, including Alzheimer’s disease (AD), are characterized by the in-brain accumulation of β-sheet structured protein aggregates called amyloids. However, neither a disease model nor therapy is established. We review past data and present new, preliminary data and opinions to help solve this problem. The following is the data-derived model/hypothesis. (1) Amyloid-forming proteins have innate immunity functions implemented by conversion to another sheet conformation, α-sheet. (2) In health, α-sheet structured, amyloid-forming proteins inactivate microbes by co-assembly with microbe α-sheets. Amyloid-forming proteins then undergo α-to-β-sheet conversion. (3) In disease, α-sheet-structured, amyloid-forming proteins over-accumulate and are neuron-toxic. This hypothesis includes formation by virus capsid subunits of α-sheets. In support, we find that 5–10 mM methylene blue (MB) at 54 °C has a hyper-expanding, thinning effect on the phage T4 capsid, as seen by negative stain- and cryo-electron microscopy after initial detection by native gel electrophoresis (AGE). Given the reported mild anti-AD effect of MB, we propose the following corollary hypothesis. (1) Anti-AD MB activity is, at least in part, caused by MB-binding to amyloid α-sheet and (2) MB induces the transition to α-sheet of T4 capsid subunits. We propose using AGE of drug incubated T4 to test for improved anti-AD activity.https://www.mdpi.com/1422-0067/25/6/3479agarose gel electrophoresisnativeamyloid-forming proteinsdisease modelingdrug effectiveness assaymolecular model |
| spellingShingle | Meagan Susanne Weaver-Rosen Philip Serwer Alzheimer’s Disease: A Molecular Model and Implied Path to Improved Therapy International Journal of Molecular Sciences agarose gel electrophoresis native amyloid-forming proteins disease modeling drug effectiveness assay molecular model |
| title | Alzheimer’s Disease: A Molecular Model and Implied Path to Improved Therapy |
| title_full | Alzheimer’s Disease: A Molecular Model and Implied Path to Improved Therapy |
| title_fullStr | Alzheimer’s Disease: A Molecular Model and Implied Path to Improved Therapy |
| title_full_unstemmed | Alzheimer’s Disease: A Molecular Model and Implied Path to Improved Therapy |
| title_short | Alzheimer’s Disease: A Molecular Model and Implied Path to Improved Therapy |
| title_sort | alzheimer s disease a molecular model and implied path to improved therapy |
| topic | agarose gel electrophoresis native amyloid-forming proteins disease modeling drug effectiveness assay molecular model |
| url | https://www.mdpi.com/1422-0067/25/6/3479 |
| work_keys_str_mv | AT meagansusanneweaverrosen alzheimersdiseaseamolecularmodelandimpliedpathtoimprovedtherapy AT philipserwer alzheimersdiseaseamolecularmodelandimpliedpathtoimprovedtherapy |