Will Schmidt

Introduction: Alzheimer’s disease (AD) is a multifactorial, progressive neurodegenerative disease of aging that accounts for approximately 80% of dementia cases¹. Genome wide association studies (GWAS) have identified over 20 mutations that increase risk of AD. Some of these mutations alter inflammatory mechanisms such as phagocytotic clearance of amyloid beta plaques (Ab), and cerebral homeostasis in response to plaques^2,3. A TREM2 mutation, R47H, was identified with increased risk of AD in European descent individuals and is due to a loss-of-function¹. Cell culture and transgenic mouse studies identified TREM2 as a receptor that enhances the rate of phagocytosis in microglia and modulates inflammatory signaling^1,2.  Thus the there is a potential therapeutic value of stimulating TREM2 in AD patients⁴. Methods In order to evaluate the role of TREM2 in Ab deposition, Song et. al generated transgenic mice expressing hTREM2 and R47H that were then crossed with KO mice and 5XFAD mice. Plaque-associated microglial density was then correlated to Ab clearance. Therapeutic effects of ALOO2a activation of TREM2 were evaluated in male 5XFAD mice by Price et. al. AL002a is a mouse IgG1 antibody that activates the TREM2 signaling pathway⁴. Cognitive changes were measured at week 12 via radial arm water maze test (RAWM) and novel object recognition tasks. Ab accumulation in the frontal cortex and hippocampus were evaluated in a subset of mice using immunohistochemistry. Neuroinflammatory response transcripts were analyzed using PCR of genes in the right hippocampus at 14 weeks in control and treated mice.  Results Higher plaque-associated microglia density was found in CV-KO-5XFAD than KO-5XFAD⁵. Similar density between KO-5XFAD and R47H-KO-5XFAD mice were observed indicating R47H reduced phagocytic clearance to the same degree of KO⁵. RAWM found significant reduction of cognitive errors in treated mice, treated mice also spent more time with familiar objects⁴. These findings correlate to increased problem solving and recognition memory⁴. PCR of AL002a treated mice found significant increase in both pro-inflammatory and anti-inflammatory gene markers indicating a homeostatic response to Ab accumulation⁴. Immunohistochemistry found reduction of total Ab in frontal cortex and hippocampus in treated compared to control⁴.  Conclusion Studies have found TREM2 plays an important role in clearance of Ab and neuroinflammatory response that may be present decades prior to AD symptoms. New studies targeting TREM2 may provide a viable treatment to slow AD progression.

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2. Hampel H, Caraci F, Cuello AC, et al. A Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer’s Disease. Front Immunol. 2020;11(21). doi:10.3389/fimmu.2020.00456
3. Kim S-M, Mun B-R, Lee S-J, et al. TREM2 promotes Aβ phagocytosis by upregulating C/EBPα-dependent CD36 expression in microglia OPEN. Korea At Energy Insitute. 29:580-185. doi:10.1038/s41598-017-11634-x
4. Price BR, Sudduth TL, Weekman EM, et al. Therapeutic Trem2 activation ameliorates amyloid-beta deposition and improves cognition in the 5XFAD model of amyloid deposition. doi:10.1186/s12974-020-01915-0
5. Song WM, Joshita S, Zhou Y, Ulland TK, Gilfillan S, Colonna M. Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism. J Exp Med. 2018;215(3):745-760. doi:10.1084/jem.20171529