Untangling the Role of TREM2 in Conjugation with Microglia in Neuronal Dysfunction: A Hypothesis on a Novel Pathway in the Pathophysiology of Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a complex neurodegenerative disorder involving heterogenous pathophysiological characteristics, which has become a challenge to therapeutics. The major pathophysiology of AD comprises amyloid-β (Aβ), tau, oxidative stress, and apoptosis. Recent studies indicate the significance of Triggering receptor expressed on myeloid cells 2 (TREM2) and its mutant variants in AD. TREM2 are the transmembrane receptors of microglial cells that performs a broad range of physiological cell processes. Phagocytosis of Aβ is one of the physiological roles of TREM2, which plays a pivotal role in AD progression. R47H, a mutant variant of TREM2, increases the risk of AD by impairing TREM2-Aβ binding. Inconclusive evidence regarding the TREM2 signaling cascade mechanism of Aβ phagocytosis motivates the current review to propose a new hypothesis. The review systematically assesses the cross talk between TREM2 and other AD pathological domains and the influence of TREM2 on amyloid and tau seeding. Disease associated microglia (DAM), a novel state of microglia with unique transcriptional and functional signatures reported in neurodegenerative conditions, also depend on the TREM2 pathway for its differentiation. DAM is suggested to have a neuroprotective role. We hypothesize that TREM2, along with its signaling adaptors and endogenous proteins, play a key role in ameliorating Aβ clearance. We indicate that TREM2 has the potential to ameliorate the Aβ burden, though with differential clearance ability and may act as a potential therapeutic target.

Keywords: Alzheimer’s disease; DAM; DAP10; DAP12; PLCγ2; R47H; TREM2; amyloid-β; disease associated microglia; microglia; neurodegeneration.

Fig. 1

Structure of TREM2–DAP adaptor complex: The figure explains the composition of TREM2 in Plasma membrane and its complex formation with DAP 10 and 12 complex. TREM2, Triggering receptor expressed on myeloid cells 2; DAP 12 and 10, DNAX activation proteins 12 and 10; ITAM, Immunoreceptor tyrosine based activation motif; YINM, tyrosine-isoleucine-asparagine-methionine; SYK, Spleen tyrosine kinase; PI3K, Phosphatidyl inositol 3-kinase; sTREM2, Soluble TREM2; ADAM 10 and 17, α-secretase-disintegrin and metalloproteinase domain containing proteins 10 and 17.

Fig. 2

Canonical signaling pathway of TREM2–DAP12 cascade and its functional role. Phosphorylation of tyrosine residues of ITAM in DAP 12 leads to the activation of SYK which results to phosphorylation of endogenous signaling proteins: ERK 1/2, Cb1, and PLCγ1. These proteins translocate to nucleus and initiates the expression of multiple transcription factors which had implications in cell survival, differentiation, and proliferation.

Fig. 3

Pathological implications in cross talk between TREM2 and other AD domains. a) Cross talk between TREM2 and Aβ. b) Cross talk between TREM2 and tau. c) Cross talk between TREM2 and APOE. d) Cross talk between TREM2 and PLCγ2. All these cross talk features play a crucial role in novel pathophysiology leading to neuronal cell dysfunction.

Fig. 4

Hypothetical mechanism of amelioratory role of TREM2 microglial receptors in Amyloid β degradation in Alzheimer’s disease. TREM2, Triggering receptor expressed on myeloid cells 2; DAP 12 and 10, DNAX activation proteins 12 and 10; ITAM, Immunoreceptor tyrosine based activation motif; YINM, tyrosine-isoleucine-asparagine-methionine; SYK, Spleen tyrosine kinase; PI3K, Phosphatidyl inositol 3-kinase; PLCγ2, Phosphatidyl inositol specific phospholipase Cγ2