Dimensional Changes in Lipid Rafts from Human Brain Cortex Associated to Development of Alzheimer’s Disease. Predictions from an Agent-Based Mathematical Model
Alzheimer’s disease (AD) is a neurodegenerative disease caused by abnormal functioning of critical physiological processes in nerve cells and aberrant accumulation of protein aggregates in the brain. The initial cause remains elusive—the only unquestionable risk factor for the most frequent variant...
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-11-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/22/12181 |
| _version_ | 1797510079350571008 |
|---|---|
| author | Guido Santos Mario Díaz |
| author_facet | Guido Santos Mario Díaz |
| author_sort | Guido Santos |
| collection | DOAJ |
| description | Alzheimer’s disease (AD) is a neurodegenerative disease caused by abnormal functioning of critical physiological processes in nerve cells and aberrant accumulation of protein aggregates in the brain. The initial cause remains elusive—the only unquestionable risk factor for the most frequent variant of the disease is age. Lipid rafts are microdomains present in nerve cell membranes and they are known to play a significant role in the generation of hallmark proteinopathies associated to AD, namely senile plaques, formed by aggregates of amyloid β peptides. Recent studies have demonstrated that human brain cortex lipid rafts are altered during early neuropathological phases of AD as defined by Braak and Braak staging. The lipid composition and physical properties of these domains appear altered even before clinical symptoms are detected. Here, we use a coarse grain molecular dynamics mathematical model to predict the dimensional evolution of these domains using the experimental data reported by our group in human frontal cortex. The model predicts significant size and frequency changes which are detectable at the earliest neuropathological stage (ADI/II) of Alzheimer’s disease. Simulations reveal a lower number and a larger size in lipid rafts from ADV/VI, the most advanced stage of AD. Paralleling these changes, the predictions also indicate that non-rafts domains undergo simultaneous alterations in membrane peroxidability, which support a link between oxidative stress and AD progression. These synergistic changes in lipid rafts dimensions and non-rafts peroxidability are likely to become part of a positive feedback loop linked to an irreversible amyloid burden and neuronal death during the evolution of AD neuropathology. |
| first_indexed | 2024-03-10T05:26:39Z |
| format | Article |
| id | doaj.art-7fd108b350c645f4890051922ffa9da9 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T05:26:39Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-7fd108b350c645f4890051922ffa9da92023-11-22T23:38:17ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-11-0122221218110.3390/ijms222212181Dimensional Changes in Lipid Rafts from Human Brain Cortex Associated to Development of Alzheimer’s Disease. Predictions from an Agent-Based Mathematical ModelGuido Santos0Mario Díaz1Systems Biology and Mathematical Modelling Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Biology Section, Science School, Universidad de La Laguna, 38200 San Cristóbal de La Laguna, SpainLaboratory of Membrane Physiology and Biophysics, Department of Animal Biology, Edaphology and Geology, Biology Section, Science School, Universidad de La Laguna, 38200 San Cristóbal de La Laguna, SpainAlzheimer’s disease (AD) is a neurodegenerative disease caused by abnormal functioning of critical physiological processes in nerve cells and aberrant accumulation of protein aggregates in the brain. The initial cause remains elusive—the only unquestionable risk factor for the most frequent variant of the disease is age. Lipid rafts are microdomains present in nerve cell membranes and they are known to play a significant role in the generation of hallmark proteinopathies associated to AD, namely senile plaques, formed by aggregates of amyloid β peptides. Recent studies have demonstrated that human brain cortex lipid rafts are altered during early neuropathological phases of AD as defined by Braak and Braak staging. The lipid composition and physical properties of these domains appear altered even before clinical symptoms are detected. Here, we use a coarse grain molecular dynamics mathematical model to predict the dimensional evolution of these domains using the experimental data reported by our group in human frontal cortex. The model predicts significant size and frequency changes which are detectable at the earliest neuropathological stage (ADI/II) of Alzheimer’s disease. Simulations reveal a lower number and a larger size in lipid rafts from ADV/VI, the most advanced stage of AD. Paralleling these changes, the predictions also indicate that non-rafts domains undergo simultaneous alterations in membrane peroxidability, which support a link between oxidative stress and AD progression. These synergistic changes in lipid rafts dimensions and non-rafts peroxidability are likely to become part of a positive feedback loop linked to an irreversible amyloid burden and neuronal death during the evolution of AD neuropathology.https://www.mdpi.com/1422-0067/22/22/12181Alzheimer diseaseBraak stagesneuropathologylipid raftslipid compositionmathematical modeling |
| spellingShingle | Guido Santos Mario Díaz Dimensional Changes in Lipid Rafts from Human Brain Cortex Associated to Development of Alzheimer’s Disease. Predictions from an Agent-Based Mathematical Model International Journal of Molecular Sciences Alzheimer disease Braak stages neuropathology lipid rafts lipid composition mathematical modeling |
| title | Dimensional Changes in Lipid Rafts from Human Brain Cortex Associated to Development of Alzheimer’s Disease. Predictions from an Agent-Based Mathematical Model |
| title_full | Dimensional Changes in Lipid Rafts from Human Brain Cortex Associated to Development of Alzheimer’s Disease. Predictions from an Agent-Based Mathematical Model |
| title_fullStr | Dimensional Changes in Lipid Rafts from Human Brain Cortex Associated to Development of Alzheimer’s Disease. Predictions from an Agent-Based Mathematical Model |
| title_full_unstemmed | Dimensional Changes in Lipid Rafts from Human Brain Cortex Associated to Development of Alzheimer’s Disease. Predictions from an Agent-Based Mathematical Model |
| title_short | Dimensional Changes in Lipid Rafts from Human Brain Cortex Associated to Development of Alzheimer’s Disease. Predictions from an Agent-Based Mathematical Model |
| title_sort | dimensional changes in lipid rafts from human brain cortex associated to development of alzheimer s disease predictions from an agent based mathematical model |
| topic | Alzheimer disease Braak stages neuropathology lipid rafts lipid composition mathematical modeling |
| url | https://www.mdpi.com/1422-0067/22/22/12181 |
| work_keys_str_mv | AT guidosantos dimensionalchangesinlipidraftsfromhumanbraincortexassociatedtodevelopmentofalzheimersdiseasepredictionsfromanagentbasedmathematicalmodel AT mariodiaz dimensionalchangesinlipidraftsfromhumanbraincortexassociatedtodevelopmentofalzheimersdiseasepredictionsfromanagentbasedmathematicalmodel |