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Chronic head injury promotes tau and amyloid‐beta pathology and accelerates cognitive decline in a humanized knock‐in model of Alzheimer's disease
Author(s) -
Chiasseu Marius,
Fesharaki Arman,
Saito Takashi,
Saido Takaomi C,
Strittmatter Stephen M
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.047623
Subject(s) - dementia , amyloid precursor protein , traumatic brain injury , chronic traumatic encephalopathy , medicine , amyloid beta , disease , neuroscience , cognitive decline , genetically modified mouse , pathogenesis , alzheimer's disease , transgene , pathology , psychology , biology , poison control , gene , concussion , psychiatry , injury prevention , genetics , environmental health
Background Clinical manifestation of Alzheimer's disease (AD) symptoms is known to reflect interactions between environmental and genetic factors. Unfortunately, preclinical modeling of AD has been relying primarily on transgenic overexpression of rare dominant mutations, with little considerations to the role the environment might play in triggering the disease. Hence the disappointing results towards translational progress in disease modifying therapies. Mild traumatic brain injury (mTBI) is a well‐known environmental risk factor for dementia, including Alzheimer’s, yet there has been limited mechanistic analysis of mTBI contribution to AD pathology. Here, we investigate the interplay between mTBI and Aβ precursor protein (APP) gene mutation in AD pathogenesis. Method We employed a knock‐in (KI) model of AD that expresses the Aß‐containing exons from human APP bearing the Swedish and Iberian ( App NL‐F/NL‐F ) mutations that we subjected to repeated mTBI (rmTBI). Injury was induced in anesthetized 4‐month‐old mice by stereotactically applying daily, a mild mechanical force on the head using a controlled cortical impactor. Impacts were applied at a speed of 5 m/s, a duration of 100 ms, and depth of 1 mm for a total of 14 days alternating between each side of the cranium. Anesthetized, uninjured genotype‐ and age‐matched mice were used as sham controls. At 3‐ and 8‐months post‐injury, cortical Aβ, phospho‐tau and Iba1 expression as well as cognitive status were assessed in the injured KI subjects. Result Our data reveal that relative to controls, rmTBI enhances accumulation of amyloid‐β and hyperphosphorylated tau inclusions, as well as neuroinflammation in KI mice, this in areas both proximal and distal to the injury site. Furthermore, novel object recognition and Morris water maze tests demonstrated that the App NL‐F/NL‐F mutations synergistically exacerbates the cognitive deficits triggered by rmTBI. Conclusion Therefore, this study demonstrates that combining genetic and environmental factors provides a more robust approach for modelling AD, and that chronic head injury substantially accelerates Alzheimer's pathology in a genetically susceptible situation.