The effects of microglia on tauopathy progression can be quantified using Nexopathy in silico (Nexis) models
Abstract The prion-like transsynaptic propagation of misfolded tau along the brain’s connectome has previously been modeled using connectome-based network diffusion models. In addition to the connectome, interactions between the general neurological “milieu” in the neurodegenerative brain and protei...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-12-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-25131-3 |
| _version_ | 1811203994035421184 |
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| author | Chaitali Anand Pedro D. Maia Justin Torok Christopher Mezias Ashish Raj |
| author_facet | Chaitali Anand Pedro D. Maia Justin Torok Christopher Mezias Ashish Raj |
| author_sort | Chaitali Anand |
| collection | DOAJ |
| description | Abstract The prion-like transsynaptic propagation of misfolded tau along the brain’s connectome has previously been modeled using connectome-based network diffusion models. In addition to the connectome, interactions between the general neurological “milieu” in the neurodegenerative brain and proteinopathic species can also contribute to pathology propagation. Such a molecular nexopathy framework posits that the distinct characteristics of neurodegenerative disorders stem from interactions between the network and surrounding molecular players. However, the effects of these modulators remain unquantified. Here, we present Nexopathy in silico (“Nexis”), a quantitative model of tau progression augmenting earlier models by including parameters of pathology propagation defined by the molecular modulators of connectome-based spread. Our Nexis:microglia model provides the first quantitative characterization of this effect on the whole brain by expanding previous models of neuropathology progression by incorporating microglial influence. We show that Trem2, but not microglial homeostasis genes, significantly improved the model’s predictive power. Trem2 appears to reduce tau accumulation rate while increasing its interregional spread from the hippocampal seed area, causing higher tau burden in the striatum, pallidum, and contralateral hippocampus. Nexis provides an improved understanding and quantification of microglial contribution to tau propagation and can be flexibly modified to include other modulators of progressive neurodegeneration. |
| first_indexed | 2024-04-12T03:05:20Z |
| format | Article |
| id | doaj.art-c6858ce3cdbe4a7fba1d24dbce41a9be |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-12T03:05:20Z |
| publishDate | 2022-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-c6858ce3cdbe4a7fba1d24dbce41a9be2022-12-22T03:50:32ZengNature PortfolioScientific Reports2045-23222022-12-0112111410.1038/s41598-022-25131-3The effects of microglia on tauopathy progression can be quantified using Nexopathy in silico (Nexis) modelsChaitali Anand0Pedro D. Maia1Justin Torok2Christopher Mezias3Ashish Raj4Department of Radiology, University of California San FranciscoDepartment of Mathematics, University of Texas at ArlingtonDepartment of Radiology, University of California San FranciscoDepartment of Neuroscience, Cold Spring Harbor LaboratoryDepartment of Radiology, University of California San FranciscoAbstract The prion-like transsynaptic propagation of misfolded tau along the brain’s connectome has previously been modeled using connectome-based network diffusion models. In addition to the connectome, interactions between the general neurological “milieu” in the neurodegenerative brain and proteinopathic species can also contribute to pathology propagation. Such a molecular nexopathy framework posits that the distinct characteristics of neurodegenerative disorders stem from interactions between the network and surrounding molecular players. However, the effects of these modulators remain unquantified. Here, we present Nexopathy in silico (“Nexis”), a quantitative model of tau progression augmenting earlier models by including parameters of pathology propagation defined by the molecular modulators of connectome-based spread. Our Nexis:microglia model provides the first quantitative characterization of this effect on the whole brain by expanding previous models of neuropathology progression by incorporating microglial influence. We show that Trem2, but not microglial homeostasis genes, significantly improved the model’s predictive power. Trem2 appears to reduce tau accumulation rate while increasing its interregional spread from the hippocampal seed area, causing higher tau burden in the striatum, pallidum, and contralateral hippocampus. Nexis provides an improved understanding and quantification of microglial contribution to tau propagation and can be flexibly modified to include other modulators of progressive neurodegeneration.https://doi.org/10.1038/s41598-022-25131-3 |
| spellingShingle | Chaitali Anand Pedro D. Maia Justin Torok Christopher Mezias Ashish Raj The effects of microglia on tauopathy progression can be quantified using Nexopathy in silico (Nexis) models Scientific Reports |
| title | The effects of microglia on tauopathy progression can be quantified using Nexopathy in silico (Nexis) models |
| title_full | The effects of microglia on tauopathy progression can be quantified using Nexopathy in silico (Nexis) models |
| title_fullStr | The effects of microglia on tauopathy progression can be quantified using Nexopathy in silico (Nexis) models |
| title_full_unstemmed | The effects of microglia on tauopathy progression can be quantified using Nexopathy in silico (Nexis) models |
| title_short | The effects of microglia on tauopathy progression can be quantified using Nexopathy in silico (Nexis) models |
| title_sort | effects of microglia on tauopathy progression can be quantified using nexopathy in silico nexis models |
| url | https://doi.org/10.1038/s41598-022-25131-3 |
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