Gene-environment interaction promotes Alzheimer's risk as revealed by synergy of repeated mild traumatic brain injury and mouse App knock-in
There is a strong unmet need for translational progress towards Alzheimer's disease (AD) modifying therapy. Unfortunately, preclinical modeling of the disease has been disappointing, relying primarily on transgenic mouse overexpression of rare dominant mutations. Clinical manifestation of AD sy...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-11-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S096999612030334X |
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| author | Marius Chiasseu Arman Fesharaki-Zadeh Takashi Saito Takaomi C. Saido Stephen M. Strittmatter |
| author_facet | Marius Chiasseu Arman Fesharaki-Zadeh Takashi Saito Takaomi C. Saido Stephen M. Strittmatter |
| author_sort | Marius Chiasseu |
| collection | DOAJ |
| description | There is a strong unmet need for translational progress towards Alzheimer's disease (AD) modifying therapy. Unfortunately, preclinical modeling of the disease has been disappointing, relying primarily on transgenic mouse overexpression of rare dominant mutations. Clinical manifestation of AD symptoms is known to reflect interaction between environmental and genetic risks. Mild traumatic brain injury (mTBI) is an environmental risk for dementia, including Alzheimer's, but there has been limited mechanistic analysis of mTBI contribution to AD. Here, we investigate the interplay between mTBI and Aβ precursor protein gene mutation in AD pathogenesis. We employed a knock-in (KI) model of AD that expresses the Aß-containing exons from human APP bearing the Swedish and Iberian mutations, namely AppNL-F/NL-F mice. Without environmental risk, this genetic variation yields minimal mouse symptomatology. Anesthetized 4-month-old KI mice and their age-matched wild type (WT) controls were subjected to repeated mild closed head injury (rmCHI), once daily for 14 days. Anesthetized, uninjured genotype- and age-matched mice were used as sham controls. At 3- and 8-months post-injury, amyloid-β, phospho-tau and Iba1 expression in the injured KI cortices were assessed. Our data reveal that rmCHI enhances accumulation of amyloid-β and hyperphosphorylated tau inclusions, as well as neuroinflammation in AppNL-F/NL-F mice. Furthermore, novel object recognition and Morris water maze tests demonstrated that rmCHI greatly exacerbates persistent cognitive deficits in APPNL-F/NL-F mice. Therefore, study of gene-environment interaction demonstrates that combining risk factors provides a more robust model for AD, and that repeated mTBI substantially accelerates AD pathology in a genetically susceptible situation. |
| first_indexed | 2024-12-16T18:46:18Z |
| format | Article |
| id | doaj.art-5da845cdca384f65940a097902777d42 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-16T18:46:18Z |
| publishDate | 2020-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-5da845cdca384f65940a097902777d422022-12-21T22:20:50ZengElsevierNeurobiology of Disease1095-953X2020-11-01145105059Gene-environment interaction promotes Alzheimer's risk as revealed by synergy of repeated mild traumatic brain injury and mouse App knock-inMarius Chiasseu0Arman Fesharaki-Zadeh1Takashi Saito2Takaomi C. Saido3Stephen M. Strittmatter4Cellular Neuroscience, Neurodegeneration and Repair Program, Yale University School of Medicine, New Haven, CT, USA; Departments of Neurology, Yale University School of Medicine, New Haven, CT, USACellular Neuroscience, Neurodegeneration and Repair Program, Yale University School of Medicine, New Haven, CT, USA; Departments of Neurology, Yale University School of Medicine, New Haven, CT, USALaboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Science, 1 Kawasumi, Mizuho-ku, Mizuho-cho, Nagoya, Aichi 467-8601, JapanLaboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako, Saitama 351-0198, JapanCellular Neuroscience, Neurodegeneration and Repair Program, Yale University School of Medicine, New Haven, CT, USA; Departments of Neurology, Yale University School of Medicine, New Haven, CT, USA; Departments of Neuroscience, Yale University School of Medicine, New Haven, CT, USA; Corresponding author at: Cellular Neuroscience, Neurodegeneration and Repair Program, Yale University School of Medicine, New Haven, CT, USA.There is a strong unmet need for translational progress towards Alzheimer's disease (AD) modifying therapy. Unfortunately, preclinical modeling of the disease has been disappointing, relying primarily on transgenic mouse overexpression of rare dominant mutations. Clinical manifestation of AD symptoms is known to reflect interaction between environmental and genetic risks. Mild traumatic brain injury (mTBI) is an environmental risk for dementia, including Alzheimer's, but there has been limited mechanistic analysis of mTBI contribution to AD. Here, we investigate the interplay between mTBI and Aβ precursor protein gene mutation in AD pathogenesis. We employed a knock-in (KI) model of AD that expresses the Aß-containing exons from human APP bearing the Swedish and Iberian mutations, namely AppNL-F/NL-F mice. Without environmental risk, this genetic variation yields minimal mouse symptomatology. Anesthetized 4-month-old KI mice and their age-matched wild type (WT) controls were subjected to repeated mild closed head injury (rmCHI), once daily for 14 days. Anesthetized, uninjured genotype- and age-matched mice were used as sham controls. At 3- and 8-months post-injury, amyloid-β, phospho-tau and Iba1 expression in the injured KI cortices were assessed. Our data reveal that rmCHI enhances accumulation of amyloid-β and hyperphosphorylated tau inclusions, as well as neuroinflammation in AppNL-F/NL-F mice. Furthermore, novel object recognition and Morris water maze tests demonstrated that rmCHI greatly exacerbates persistent cognitive deficits in APPNL-F/NL-F mice. Therefore, study of gene-environment interaction demonstrates that combining risk factors provides a more robust model for AD, and that repeated mTBI substantially accelerates AD pathology in a genetically susceptible situation.http://www.sciencedirect.com/science/article/pii/S096999612030334XAlzheimer's diseaseRepeated mild traumatic brain injuryAmyloid-betaTau proteinNeuroinflammationCognitive decline |
| spellingShingle | Marius Chiasseu Arman Fesharaki-Zadeh Takashi Saito Takaomi C. Saido Stephen M. Strittmatter Gene-environment interaction promotes Alzheimer's risk as revealed by synergy of repeated mild traumatic brain injury and mouse App knock-in Neurobiology of Disease Alzheimer's disease Repeated mild traumatic brain injury Amyloid-beta Tau protein Neuroinflammation Cognitive decline |
| title | Gene-environment interaction promotes Alzheimer's risk as revealed by synergy of repeated mild traumatic brain injury and mouse App knock-in |
| title_full | Gene-environment interaction promotes Alzheimer's risk as revealed by synergy of repeated mild traumatic brain injury and mouse App knock-in |
| title_fullStr | Gene-environment interaction promotes Alzheimer's risk as revealed by synergy of repeated mild traumatic brain injury and mouse App knock-in |
| title_full_unstemmed | Gene-environment interaction promotes Alzheimer's risk as revealed by synergy of repeated mild traumatic brain injury and mouse App knock-in |
| title_short | Gene-environment interaction promotes Alzheimer's risk as revealed by synergy of repeated mild traumatic brain injury and mouse App knock-in |
| title_sort | gene environment interaction promotes alzheimer s risk as revealed by synergy of repeated mild traumatic brain injury and mouse app knock in |
| topic | Alzheimer's disease Repeated mild traumatic brain injury Amyloid-beta Tau protein Neuroinflammation Cognitive decline |
| url | http://www.sciencedirect.com/science/article/pii/S096999612030334X |
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