A Trem2R47H mouse model without cryptic splicing drives age- and disease-dependent tissue damage and synaptic loss in
Kristine M Tran1, Shimako Kawauchi2,3, Enikö A Kramár1
1Department of Neurobiology and Behavior, University of California, Irvine, USA.
Background:
The TREM2 R47H variant is one of the strongest genetic risk factors for late-onset Alzheimer's Disease (AD). Unfortunately, many current Trem2 R47H mouse 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 the Trem2R47H NSS (Normal Splice Site) mouse model in which the Trem2 allele is expressed at a similar level to the wild-type Trem2 allele without evidence of cryptic splicing products.
Methods:
Trem2R47H NSS mice 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.
Results:
Trem2R47H NSS mice 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 in Trem2R47H NSS mice in response to development of AD-like pathology. At an early (4-month-old) disease stage, hemizygous 5xFAD/homozygous Trem2R47H 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 for Trem2R47H NSS suppressed 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 NSS mice 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 old Trem2R47H NSS mice also display LTP deficits and postsynaptic loss.
Conclusions:
The Trem2R47H NSS mouse 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.
Insights
The novel Trem2R47H NSS mouse model accurately reflects TREM2 R47H Alzheimer's Disease (AD) risk without splicing issues. This model reveals age-dependent microglial and inflammatory changes in response to AD pathology.
Area of Science:
- Neuroscience
- Genetics
- Immunology
Background:
- The TREM2 R47H variant is a significant genetic risk factor for late-onset Alzheimer's Disease (AD).
- Existing Trem2R47H mouse models exhibit cryptic mRNA splicing, reducing protein product and confounding research.
- A new Trem2R47H NSS (Normal Splice Site) mouse model was developed to express Trem2 at wild-type levels without splicing anomalies.
Purpose of the Study:
- To develop a reliable mouse model for studying the TREM2 R47H variant's impact on Alzheimer's Disease (AD) pathogenesis.
- To investigate the role of TREM2 R47H in inflammatory responses to demyelination and amyloid plaque development.
- To analyze the age- and disease-dependent effects of TREM2 R47H on microglial function and brain pathology.
Main Methods:
- The Trem2R47H NSS mouse model was utilized.
- Mice were treated with the demyelinating agent cuprizone.
- Mice were crossed with the 5xFAD mouse model of amyloidosis to study AD-like pathology.
Main Results:
- Trem2R47H NSS mice showed appropriate inflammatory responses to cuprizone-induced demyelination.
- In 5xFAD/Trem2R47H NSS mice, early-stage pathology (4 months) revealed reduced microglia interacting with plaques, suppressed inflammation, and increased axonal damage (elevated NfL).
- Later-stage pathology (12 months) showed restored plaque-microglia interaction and inflammatory gene expression, but persistent elevated NfL and a unique interferon signature were observed.
Conclusions:
- The Trem2R47H NSS mouse is a valuable tool for studying the age-dependent effects of the AD-risk R47H mutation on TREM2 and microglial function.
- This model facilitates research into TREM2 R47H's impact on plaque development, microglial-plaque interaction, and associated tissue damage.
- The model highlights the production of a unique interferon signature linked to TREM2 R47H and tissue damage in AD.
