Triggering receptor expressed on myeloid cells 2 (TREM2): a potential therapeutic target for Alzheimer disease?

ABSTRACT

Introduction: There are currently no effective therapeutics for Alzheimer disease (AD). Clinical trials targeting amyloid beta thus far have shown very little benefit and only in the earliest stages of disease. These limitations have driven research to identify alternative therapeutic targets, one of the most promising is the triggering receptor expressed on myeloid cells 2 (TREM2).

Areas covered: Here, we review the literature to-date and discuss the potentials and pitfalls for targeting TREM2 as a potential therapeutic for AD. We focus on research in animal and cell models for AD and central nervous system injury models which may help in understanding the role of TREM2 in disease.

Expert opinion: Studies suggest TREM2 plays a key role in AD pathology; however, results have been conflicting about whether TREM2 is beneficial or harmful. More research is necessary before designing TREM2-targeting therapies. Successful therapeutics will most likely be administered early in disease.

KEYWORDS:

• TREM2
• Alzheimer disease
• cerebrospinal fluid
• genetic association
• microglia

Article Highlights

• Vaccines targeting amyloid have reached phase 3 clinical trials but have currently shown little or no improvement in cognitive symptoms, leading researchers to search for alternative AD therapeutics.

• Since pathology appears years before cognitive symptoms, treatments for AD most likely need to be administered early in disease to be affective.

• TREM2 has been strongly associated with AD and plays a key role in innate immune response; however, the exact mechanisms are unclear. There is conflicting evidence about whether TREM2-targeted therapeutics should enhance or downregulate expression of TREM2.

• Context is important for understanding the role of TREM2 in AD; microglial activation state, presence of amyloid-mediated or tau-mediated pathology, and acute versus chronic injury can all have different effects that can be beneficial or harmful.

• Most research to-date has explored Trem2 knockout/knockdown; however, it has been demonstrated that different TREM2 mutations associated with disease influence sTREM2 levels differently. More research using transgenic models studying identified TREM2 mutations is necessary.

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Declaration of interests

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewers disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This manuscript is supported by grants from the National Institutes of Health (NIH) [R01-AG044546, P01-AG003991, U01-AG05241102, and RF1-AG053303], the Alzheimer Association [NIRG-11-200110, BAND-14-338165, and BFG-15-362540]. Y Deming is supported by an NIMH training grant [T32MH014877]. BA Benitez is supported by 2018 pilot funding from the Hope Center for Neurological Disorders and the Danforth Foundation Challenge at Washington University.