BackgroundGenetic variants of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) confer increased risk of developing late-onset Alzheimer’s Disease (LOAD) and other neurodegenerative disorders. Recent studies provided insight into the multifaceted roles of TREM2 in regulating extracellular β-amyloid (Aβ) pathology, myeloid cell accumulation, and inflammation observed in AD, yet little is known regarding the role of TREM2 in regulating intracellular microtubule associated protein tau (MAPT; tau) pathology in neurodegenerative diseases and in AD, in particular.ResultsHere we report that TREM2 deficiency leads to accelerated and exacerbated hyperphosphorylation and aggregation of tau in a humanized mouse model of tauopathy. TREM2 deficiency also results, indirectly, in dramatic widespread dysregulation of neuronal stress kinase pathways.ConclusionsOur results suggest that deficiency of microglial TREM2 leads to heightened tau pathology coupled with widespread increases in activated neuronal stress kinases. These findings offer new insight into the complex, multiple roles of TREM2 in regulating Aβ and tau pathologies.Electronic supplementary materialThe online version of this article (10.1186/s13024-017-0216-6) contains supplementary material, which is available to authorized users.

No abstract

Recent reports in Alzheimer's disease (AD) research suggest that alterations in microRNA (miRNA) expression are associated with disease pathology. Our previous studies suggest that A Disintegrin and Metalloproteinase 10 (ADAM10) expression is important in AD and could be modulated by an extended regulatory region that includes the 3' untranslated region. In this study, we have investigated the role of trans-acting factors in ADAM10 gene regulation. Our study shows that miRNA-140-5p has enhanced expression in the AD postmortem brain hippocampus using high-throughput miRNA arrays and quantitative real-time polymerase chain reaction. Interestingly, we have also seen that miRNA-140-5p seed sequence is present on 3' untranslated region of both ADAM10 and its transcription factor SOX2. The specific interaction of miRNA-140-5p with both ADAM10 and SOX2 signifies high regulatory importance of this miRNA in controlling ADAM10 expression. Thus, this investigation unravels mechanisms underlying ADAM10 downregulation by miR-140-5p and suggests that dysfunctional regulation of ADAM10 expression is exacerbated by AD-related neurotoxic effects. These findings underscore the importance of understanding the impact of trans-acting factors in the modulation of AD pathophysiology.

BackgroundFractalkine (CX3CL1) and its receptor (CX3CR1) play an important role in regulating microglial function. We have previously shown that Cx3cr1 deficiency exacerbated tau pathology and led to cognitive impairment. However, it is still unclear if the chemokine domain of the ligand CX3CL1 is essential in regulating neuronal tau pathology.MethodsWe used transgenic mice lacking endogenous Cx3cl1 (Cx3cl1−/−) and expressing only obligatory soluble form (with only chemokine domain) and lacking the mucin stalk of CX3CL1 (referred to as Cx3cl1105Δ mice) to assess tau pathology and behavioral function in both lipopolysaccharide (LPS) and genetic (hTau) mouse models of tauopathy.ResultsFirst, increased basal tau levels accompanied microglial activation in Cx3cl1105Δ mice compared to control groups. Second, increased CD45+ and F4/80+ neuroinflammation and tau phosphorylation were observed in LPS, hTau/Cx3cl1−/−, and hTau/Cx3cl1105Δ mouse models of tau pathology, which correlated with impaired spatial learning. Finally, microglial cell surface expression of CX3CR1 was reduced in Cx3cl1105Δ mice, suggesting enhanced fractalkine receptor internalization (mimicking Cx3cr1 deletion), which likely contributes to the elevated tau pathology.ConclusionsCollectively, our data suggest that overexpression of only chemokine domain of CX3CL1 does not protect against tau pathology.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1310-6) contains supplementary material, which is available to authorized users.

Alzheimer’s disease (AD) is characterized by the accumulation in the brain of extracellular amyloid β (Aβ) plaques as well as intraneuronal inclusions (neurofibrillary tangles) consisting of total tau and phosphorylated tau. Also present are dystrophic neurites, loss of synapses, neuronal death, and gliosis. AD genetic studies have highlighted the importance of inflammation in this disease by identifying several risk associated immune response genes, including TREM2. TREM2 has been strongly implicated in basic microglia function including, phagocytosis, apoptosis, and the inflammatory response to Aβ in mouse brain and primary cells. These studies show that microglia are key players in the response to Aβ and in the accumulation of AD pathology. However, details are still missing about which apoptotic or inflammatory factors rely on TREM2 in their response to Aβ, especially in human cell lines. Given these previous findings our hypothesis is that TREM2 influences the response to Aβ toxicity by enhancing phagocytosis and inhibiting both the BCL-2 family of apoptotic proteins and pro-inflammatory cytokines. Aβ42 treatment of the human microglial cell line, HMC3 cells, was performed and TREM2 was overexpressed or silenced and the phagocytosis, apoptosis and inflammatory response were evaluated. Results indicate that a robust phagocytic response to Aβ after 24 hours requires TREM2 in HMC3 cells. Also, TREM2 inhibits Aβ induced apoptosis by activating the Mcl-1/Bim complex. TREM2 is involved in activation of IP-10, MIP-1a, and IL-8, while it inhibits FGF-2, VEGF and GRO. Taken together, TREM2 plays a role in enhancing the microglial functional response to Aβ toxicity in HMC3 cells. This novel information suggests that therapeutic strategies that seek to activate TREM2 may not only enhance phagocytosis, but it may also inhibit beneficial inflammatory factors, emphasizing the need to define TREM2-related inflammatory activity in not only mouse models of AD, but also in human AD.