Alzheimer?s disease (AD) is the most common neurodegenerative disorder. Although AD patients feature amyloid plaques and neurofibrillary tangles comprising neurotoxic components such as A? and tau within varying brain regions, components which drive neurodegenerative onset during early stages of AD remain uncertain. Interestingly, genome-wide association studies (GWAS) have uncovered a variety of genes enriched in microglia and myeloid cell types, suggesting that AD may be modulated by microglial activation and function. One particular microglial transmembrane component, TREM2 (Triggering Receptor Expressed on Myeloid cells 2) identified by GWAS presents an interesting case for study as mutations in its ectodomain has been implicated in AD, Nasu-Hakola disease, and frontotemporal dementia. Given that these disorders feature neuroinflammatory etiologies, it seems likely that TREM2 microglial function may modulate neurodegenerative onset. TREM2 is proteolytically processed by ADAM proteases to generate soluble TREM2 (sTREM2) ectodomain fragments. Interestingly, sTREM2 levels have been found to be significantly elevated cerebrospinal fluid (CSF) during early stages of AD onset, and its levels correlate with pathogenic CSF markers such as tau and its hyperphosphorylated forms. Despite the potential use of sTREM2 as an early- stage AD biomarker, virtually nothing is known with regards to its role in microglial or neuronal function. Here we present evidence that sTREM2 can enhance microglial survival and activation to enhance proinflammatory cytokine expression. We also find that sTREM2 expression is induced by oligomerized tau, and exposure to sTREM2 can inhibit A? uptake. With these findings, we hypothesize that sTREM2 can act as a modulator of AD onset, and can thereby influence pathogenic A? plaque deposition/clearance, cognitive behavior, and synaptic function. Since little is known with regards to how sTREM2 is generated, and whether sTREM2 or the sTREM2 R47H risk variant can modulate microglial and neuronal function, we present aims here to define neuropathogenic conditions that may influence sTREM2 induction, and trafficking pathways that may influence sTREM2 generation. We will then determine the effects of sTREM2 on microglial and neuronal function. Using inducible microglial and macrophage sTREM2/sTREM2 R47H overexpression mouse models in AD APP/PS1 or tauopathic P301S Tau-Tg backgrounds, we will then determine whether sTREM2 can modulate cognitive behavior, pathological A?/tau accumulation, and synaptic decline. Together, completion of these aims will derive mechanisms of sTREM2 generation, and consequential effects on microglial and neuronal function. Using inducible sTREM2 mouse models, we will also be able to discern sTREM2 modulatory effects on cognitive, pathological and synaptic decline with AD stress. This will provide evidence that correlative increases in sTREM2 levels observed in early-stage AD will influence AD onset and outcome.

Public Health Relevance

TREM2 is a genetic risk factor for Alzheimer?s disease (AD), where elevated levels of a cleaved soluble TREM2 (sTREM2) form is found to be elevated in cerebrospinal fluid in early stage AD patients. The purpose of the current study here is to characterize mechanisms underlying sTREM2 generation, and to determine the effects of sTREM2 in cultured neurons and microglia, and in inducible sTREM2 mouse expression models in a proteotoxic AD context. The sum of this study will establish a role for sTREM2 in AD progression, and may present an early stage AD target to attenuate AD onset.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Multi-Year Funded Research Project Grant (RF1)
Project #
1RF1AG056130-01
Application #
9334000
Study Section
Special Emphasis Panel (ZRG1-MDCN-E (07)R)
Program Officer
Yang, Austin Jyan-Yu
Project Start
2017-04-01
Project End
2022-03-31
Budget Start
2017-04-01
Budget End
2022-03-31
Support Year
1
Fiscal Year
2017
Total Cost
$3,404,918
Indirect Cost
$927,542
Name
Sanford Burnham Prebys Medical Discovery Institute
Department
Type
Research Institutes
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Kang, Silvia S; Kurti, Aishe; Baker, Kelsey E et al. (2018) Behavioral and transcriptomic analysis of Trem2-null mice: not all knockout mice are created equal. Hum Mol Genet 27:211-223
Lee, C Y Daniel; Daggett, Anthony; Gu, Xiaofeng et al. (2018) Elevated TREM2 Gene Dosage Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer's Disease Models. Neuron 97:1032-1048.e5
Du, Ying; Zhao, Yingjun; Li, Chuan et al. (2018) Inhibition of PKC? reduces amyloid-? levels and reverses Alzheimer disease phenotypes. J Exp Med 215:1665-1677
Simandi, Zoltan; Pajer, Krisztian; Karolyi, Katalin et al. (2018) Arginine Methyltransferase PRMT8 Provides Cellular Stress Tolerance in Aging Motoneurons. J Neurosci 38:7683-7700
Zhao, Yingjun; Wu, Xilin; Li, Xiaoguang et al. (2018) TREM2 Is a Receptor for ?-Amyloid that Mediates Microglial Function. Neuron 97:1023-1031.e7
Zhao, Yingjun; Li, Xiaoguang; Huang, Timothy et al. (2017) Intracellular trafficking of TREM2 is regulated by presenilin 1. Exp Mol Med 49:e405
Liu, Chia-Chen; Zhao, Na; Fu, Yuan et al. (2017) ApoE4 Accelerates Early Seeding of Amyloid Pathology. Neuron 96:1024-1032.e3
Zheng, Honghua; Jia, Lin; Liu, Chia-Chen et al. (2017) TREM2 Promotes Microglial Survival by Activating Wnt/?-Catenin Pathway. J Neurosci 37:1772-1784
Zhong, Li; Chen, Xiao-Fen; Wang, Tingting et al. (2017) Soluble TREM2 induces inflammatory responses and enhances microglial survival. J Exp Med 214:597-607
Zhong, Li; Zhang, Zhen-Lian; Li, Xinxiu et al. (2017) TREM2/DAP12 Complex Regulates Inflammatory Responses in Microglia via the JNK Signaling Pathway. Front Aging Neurosci 9:204