Microglial TYROBP/DAP12 in Alzheimer's disease: Transduction of physiological and pathological signals across TREM2

Abstract

TYROBP (also known as DAP12 or KARAP) is a transmembrane adaptor protein initially described as a receptor-activating subunit component of natural killer (NK) cells. TYROBP is expressed in numerous cell types, including peripheral blood monocytes, macrophages, dendritic cells, and osteoclasts, but a key point of recent interest is related to the critical role played by TYROBP in the function of many receptors expressed on the plasma membrane of microglia. TYROBP is the downstream adaptor and putative signaling partner for several receptors implicated in Alzheimer's disease (AD), including SIRP1β, CD33, CR3, and TREM2. TYROBP has received much of its current notoriety because of its importance in brain homeostasis by signal transduction across those receptors. In this review, we provide an overview of evidence indicating that the biology of TYROBP extends beyond its interaction with these four ligand-binding ectodomain-intramembranous domain molecules. In addition to reviewing the structure and localization of TYROBP, we discuss our recent progress using mouse models of either cerebral amyloidosis or tauopathy that were engineered to be TYROBP-deficient or TYROBP-overexpressing. Remarkably, constitutively TYROBP-deficient mice provided a model of genetic resilience to either of the defining proteinopathies of AD. Learning behavior and synaptic electrophysiological function were preserved at normal physiological levels even in the face of robust cerebral amyloidosis (in APP/PSEN1;Tyrobp^-/- mice) or tauopathy (in MAPT^P301S;Tyrobp^-/- mice). A fundamental underpinning of the functional synaptic dysfunction associated with each proteotype was an accumulation of complement C1q. TYROBP deficiency prevented C1q accumulation associated with either proteinopathy. Based on these data, we speculate that TYROBP plays a key role in the microglial sensome and the emergence of the disease-associated microglia (DAM) phenotype. TYROBP may also play a key role in the loss of markers of synaptic integrity (e.g., synaptophysin-like immunoreactivity) that has long been held to be the feature of human AD molecular neuropathology that most closely correlates with concurrent clinical cognitive function.

Keywords: Alzheimer; Amyloid; ApoE; Complement C1q; Disease-Associated Microglia (DAM); Sensome; Tau; Trem2; Tyrobp/Dap12; miR-155.

Fig. 1

TYROBP structure and signaling pathway. Left panel: Mouse and human TYROBP: the TYROBP protein consists of a 27-aa leader peptide, a small 14-aa (16-aa in mouse, in blue) extracellular region, a 24-aa transmembrane segment, and a 48-aa (49-aa in mouse) cytoplasmic domain. Because of two cysteine residues (Cys33/35) in its extracellular region, TYROBP forms a disulfide-bonded homodimeric complex. TYROBP contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic region. Right panel: Following ligand-binding by a TYROBP-associated receptor, the ITAM motif can be phosphorylated on its two conserved tyrosine residues by SRC kinases and induce the intracellular recruitment and activation of the spleen tyrosine kinase (SYK). Upon SYK recruitment, several downstream effector molecules such as phosphatidylinositol 3-kinase (PI3K), the small GTPase RAS, or the phospholipase Cγ (PLCγ) are mobilized, resulting in activation of transcription, proliferation, release of cytokines, and phagocytosis. Abbreviations: DAG, diacylglycerol; ERK, extracellular signal-regulated kinase; IP3, inositol trisphosphate; ITAM, immunoreceptor tyrosine-based activation motif; MEK, mitogen-activated protein kinase kinase; PI3K, phosphatidylinositol 3-kinase; PIP3, phosphatidylinositol-3,4,5-trisphosphate; PLCγ, phospholipase Cγ; SYK, spleen tyrosine kinase; TYROBP, tyrosine kinase binding protein; Y, Tyrosine

Fig. 2

TYROBP influences AD pathology in standard AD-related mouse models of cerebral amyloidosis or tauopathy. In APP/PSEN1 mice, absence of TYROBP decreased microglial recruitment around Aβ deposits. APP/PSEN1 mice overexpressing TYROBP showed decreased Aβ load. In MAPT^P301S (PS19) mice, both absence and overexpression of TYROBP increased the stoichiometry of phosphorylation of TAU. While observations of these TAU phenotypic effects are usually associated with worsening clinical phenotype, absence of Tyrobp decreased the expression of C1q, the initiating protein in the classical complement cascade, and improved learning behavior and synaptic function in both amyloidosis and tauopathy mouse models. Abbreviations: TYROBP, tyrosine kinase binding protein; C1q, Complement component 1q; WT, Wildtype; KO, Knockout; DHPG, Dihydroxyphenylglycine

Fig. 3

Probable ligand-induced TYROBP signaling in recruited microglia. Ligand-induced TYROBP signaling is initiated by apolipoprotein E, Aβ, debris, or other currently unidentified ligands at sensing receptors and leads to phosphorylation of the tyrosine residues in the cytoplasmic ITAM of TYROBP by SRC kinases and the recruitment of SYK. In turn, SYK signaling can increase transcription of Tyrobp and ApoE. This series of events forms the basis for the phenotypic switch from homeostatic microglia to DAM and may be in part post-transcriptionally regulated by miR-155. We speculate that in mice lacking Trem2, recruited microglia cause other receptor ectodomains to acquire sensing capability either because these receptors always signal by complexing with TYROBP, or because signals across other complexes are induced as a compensatory mechanism due to the absence of Trem2. Abbreviations: APOE, apolipoprotein E; C1q, complement protein C1q; Ccl6, C-C motif chemokine ligand 6; Cd52, CD52 molecule; Cd68, CD68 molecule; Clec7a, C-Type lectin domain containing 7A; Csf1, colony stimulating factor 1; Cst7, cystatin F; Ctsd, cathepsin D; Ctss, cathepsin S; Ctsz, cathepsin Z; DAM, disease-associated microglia; Hexb, hexosaminidase subunit beta; ITAM, immunoreceptor tyrosine-based activation motif; Itgax, integrin subunit alpha X; Itgb2, integrin subunit beta 2; Lyz2, lysozyme 2; miR-155, microRNA-155; SYK, spleen tyrosine kinase; TREM2, triggering receptor expressed on myeloid cells-2; TYROBP, tyrosine kinase binding protein; Y, tyrosine. Adapted and reprinted with permission from Wiley Publishing, Hoboken, NJ