Abstract
AbstractBackgroundThe TREM2 R47H variant is one of the strongest genetic risk factors for late-onset Alzheimer’s Disease (AD). Unfortunately, many currentTrem2R47Hmouse models are associated with cryptic mRNA splicing of the mutant allele that produces a confounding reduction in protein product. To overcome this issue, we developed theTrem2R47H NSS(NormalSpliceSite) mouse model in which theTrem2allele is expressed at a similar level to the wild-typeTrem2allele without evidence of cryptic splicing products.MethodsTrem2R47H NSSmice were treated with the demyelinating agent cuprizone, or crossed with the 5xFAD mouse model of amyloidosis, to explore the impact of the TREM2 R47H variant on inflammatory responses to demyelination, plaque development, and the brain’s response to plaques.ResultsTrem2R47H NSSmice display an appropriate inflammatory response to cuprizone challenge, and do not recapitulate the null allele in terms of impeded inflammatory responses to demyelination. Utilizing the 5xFAD mouse model, we report age- and disease-dependent changes inTrem2R47H NSSmice in response to development of AD-like pathology. At an early (4-month-old) disease stage, hemizygous 5xFAD/homozygousTrem2R47H NSS(5xFAD/Trem2R47H NSS) mice have reduced size and number of microglia that display impaired interaction with plaques compared to microglia in age-matched 5xFAD hemizygous controls. This is associated with a suppressed inflammatory response but increased dystrophic neurites and axonal damage as measured by plasma neurofilament light chain (NfL) level. Homozygosity forTrem2R47H NSSsuppressed LTP deficits and loss of presynaptic puncta caused by the 5xFAD transgene array in 4-month-old mice. At a more advanced (12-month-old) disease stage 5xFAD/Trem2R47H NSSmice no longer display impaired plaque-microglia interaction or suppressed inflammatory gene expression, although NfL levels remain elevated, and a unique interferon-related gene expression signature is seen. Twelve-month oldTrem2R47H NSSmice also display LTP deficits and postsynaptic loss.ConclusionsTheTrem2R47H NSSmouse is a valuable model that can be used to investigate age-dependent effects of the AD-risk R47H mutation on TREM2 and microglial function including its effects on plaque development, microglial-plaque interaction, production of a unique interferon signature and associated tissue damage.
Funder
National Resource Center on Nutrition and Aging
National Institute of Neurological Disorders and Stroke
National Institute on Aging
Publisher
Springer Science and Business Media LLC
Subject
Cellular and Molecular Neuroscience,Neurology (clinical),Molecular Biology
Cited by
4 articles.
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