Alzheimer disease (AD) is the most common cause of dementia and is characterized by extracellular plaques formed by the deposition of amyloid-? (A?) peptide and intracellular tangles comprised of hyperphosphorylated forms of the tau protein. Gliosis and inflammation are associated with areas of heavy pathology and likely play a key role in shaping disease progression. Microglia, the immune cells of the central nervous system (CNS), are increasingly recognized for their critical roles in the pathogenesis of AD and other neurodegenerative diseases such as frontotemporal dementia (FTD) and Parkinson disease (PD). The strongest genetic risk factor for both AD and CAA is ?4 allele of the apolipoprotein E (APOE) gene, but recently the TREM2 locus was identified as a risk factor for AD with the most significantly associated coding variant as rs75932628 (encoding R47H) with an odds ratio rivaling that of APOE. Because human and mouse Trem2 differ by ~25% at the amino acid level, we aim to create novel knock-in mouse lines that express normal human TREM2 or the TREM2-R47H variant in place of the endogenous mouse Trem2 locus. Characterizing these novel lines along with our existing Trem2-/- mouse line either at baseline or upon immune stimulation will allow us to fundamentally answer whether the TREM2-R47H variant functions as a loss of function or gain of function. Additionally, we have recently found that TREM2 can serve as a receptor for lipoproteins. These mice will be critical in developing new therapeutics that target TREM2 in the context of neurodegeneration and in testing the functional effects of lipoprotein binding to normal vs R47H variant of TREM2.
Alzheimer disease, frontotemporal dementia, Parkinson disease, and amyotrophic lateral sclerosis are characterized by the accumulation of toxic forms of proteins eventually resulting in neuronal cell death. Recently a mutant version of a gene, TREM2, was discovered that profoundly affects the course of Alzheimer's disease, but it is unknown how this mutation affects the function of TREM2. This proposal aims to determine precisely how this mutant version of TREM2 alters the function in vivo by inserting it into the mouse genome and determining how this receptor functions upon lipoprotein binding.
| Kang, Silvia S; Ebbert, Mark T W; Baker, Kelsey E et al. (2018) Microglial translational profiling reveals a convergent APOE pathway from aging, amyloid, and tau. J Exp Med 215:2235-2245 |
| Ebbert, Mark T W; Farrugia, Stefan L; Sens, Jonathon P et al. (2018) Long-read sequencing across the C9orf72 'GGGGCC' repeat expansion: implications for clinical use and genetic discovery efforts in human disease. Mol Neurodegener 13:46 |
| Kang, S S; Ren, Y; Liu, C-C et al. (2018) Lipocalin-2 protects the brain during inflammatory conditions. Mol Psychiatry 23:344-350 |
| Wojtas, Aleksandra M; Kang, Silvia S; Olley, Benjamin M et al. (2017) Loss of clusterin shifts amyloid deposition to the cerebrovasculature via disruption of perivascular drainage pathways. Proc Natl Acad Sci U S A 114:E6962-E6971 |
