Increased expression of <scp>TREM</scp>2 in peripheral cells from mild cognitive impairment patients who progress into Alzheimer's disease

Casati, Martina; Ferri, Evelyn; Gussago, Cristina; Mazzola, Paolo; Abbate, Carlo; Bellelli, Giuseppe; Mari, Daniela; Cesari, Matteo

doi:10.1111/ene.13583

Cited by 57 publications

(36 citation statements)

References 36 publications

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“…Presently, the clinical relevance of an elevated serum sTREM2 level in AD is unknown [34]. Several studies have reported the sTREM2 level in the peripheral blood to be higher in AD patients than that in healthy individuals [47,48], whereas other investigators reported no significant difference [24,46]. This discrepancy may be attributed to the designation of groups, as important patient characteristics (i.e., gender, age, and disease stage) may affect the results.…”

Section: Localization Of Strem2mentioning

confidence: 98%

TREM2 ectodomain and its soluble form in Alzheimer’s disease

Yang

Zhang

et al. 2020

J Neuroinflammation

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Triggering receptor expressed on myeloid cells 2 (TREM2) is a receptor mainly expressed on the surface of microglia. It mediates multiple pathophysiological processes in various diseases. Recently, TREM2 has been found to play a role in the development of Alzheimer's disease (AD). TREM2 is a transmembrane protein that is specifically expressed on microglia in the brain. It contains a long ectodomain that directly interacts with the extracellular environment to regulate microglial function. The ectodomain of TREM2 is processed by a disintegrin and metalloprotease, resulting in the release of a soluble form of TREM2 (sTREM2). Recent studies have demonstrated that sTREM2 is a bioactive molecule capable of binding ligands, activating microglia, and regulating immune responses during the AD continuum. Clinical studies revealed that sTREM2 level is elevated in cerebrospinal fluid (CSF) of AD patients, and the sTREM2 level is positively correlated with the levels of classical CSF biomarkers, namely t-tau and p-tau, indicating that it is a reliable predictor of the early stages of AD. Herein, we summarize the key results on the generation, structure, and function of sTREM2 to provide new insights into TREM2-related mechanisms underlying AD pathogenesis and to promote the development of TREM2-based therapeutic strategy.

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Section: Localization Of Strem2mentioning

confidence: 98%

TREM2 ectodomain and its soluble form in Alzheimer’s disease

Yang

Zhang

et al. 2020

J Neuroinflammation

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“…AD-associated mutations lead to TREM2 dysfunction, so that microgliosis is compromised in such mutation-carrying patients and related AD model mice 31 , 32 . Both increased and decreased DNA methylation in the TREM2 gene have been reported 33 – 36 , though increased TREM2 expression has been consistently found in AD patients and mouse models and may be associated with the recruitment of microglia to amyloid plaques 37 . Moreover, TREM2 deficiency has been found to impair mTOR activation, increase autophagy, and cause metabolic dysfunctions in microglia 18 , 20 , 38 .…”

Section: Introductionmentioning

confidence: 99%

TMEM59 interacts with TREM2 and modulates TREM2-dependent microglial activities

et al. 2020

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The surface receptor triggering receptor expressed on myeloid cells 2 (TREM2) plays a crucial role in maintaining a multitude of microglial activities, such as survival, proliferation, migration, metabolism, inflammation, and phagocytosis. However, the molecular mechanisms underlying TREM2-mediated microglial activities remain largely elusive. Herein, we found that TREM2 interacted with the type I transmembrane protein TMEM59, whose expression could facilitate autophagic flux through its carboxyl-terminus. TMEM59 expression was decreased upon lipopolysaccharide treatment. While downregulation of TMEM59 promoted anti-inflammatory factor expression and attenuated lipopolysaccharide treatment-induced inflammation. Importantly, we found that overexpression of TREM2 reduced TMEM59 protein levels through promoting its degradation, whereas TMEM59 levels were elevated in Trem2deficient microglia. Finally, impaired survival, proliferation, migration, and phagocytosis, as well as dysregulated autophagy and metabolism in Trem2-deficient microglia were attenuated upon TMEM59 silencing. Together, our findings reveal a novel function of TREM2 in mediating TMEM59 protein degradation and demonstrate the importance of TMEM59 homeostasis in maintaining TREM2-mediated microglial activities.

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“…CSF YKL-40 levels negatively correlated with cortical thickness in specific AD-vulnerable areas, such as middle and inferior temporal areas in Aβ42-positive subjects [166] and grey matter volume in APOE ε4 carriers [167]. Interestingly, a positive association between CSF YKL-40 and t-tau has been reported in asymptomatic preclinical stages of AD and other NDDs [110,168], thus suggesting a link of YKL-40 with an underlying tau-driven neurodegenerative mechanisms [169].…”

Section: Biomarkers For Neuroinflammationmentioning

confidence: 97%

“…Unfortunately, plasma YKL-40 did not, so far, demonstrate utility as a diagnostic biomarker and for predicting cognitive decline (Table 2) [170,172]. To sum up, YKL-40 is an unspecific pathophysiological biomarker tracking immune/inflammatory response in NDDs, and it could be helpful as a monitoring biomarker for targeted anti-inflammatory therapies [169].…”

Section: Biomarkers For Neuroinflammationmentioning

confidence: 99%

Fluid Candidate Biomarkers for Alzheimer’s Disease: A Precision Medicine Approach

Prete

Beatino

Campese

et al. 2020

JPM

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A plethora of dynamic pathophysiological mechanisms underpins highly heterogeneous phenotypes in the field of dementia, particularly in Alzheimer’s disease (AD). In such a faceted scenario, a biomarker-guided approach, through the implementation of specific fluid biomarkers individually reflecting distinct molecular pathways in the brain, may help establish a proper clinical diagnosis, even in its preclinical stages. Recently, ultrasensitive assays may detect different neurodegenerative mechanisms in blood earlier. ß-amyloid (Aß) peptides, phosphorylated-tau (p-tau), and neurofilament light chain (NFL) measured in blood are gaining momentum as candidate biomarkers for AD. P-tau is currently the more convincing plasma biomarker for the diagnostic workup of AD. The clinical role of plasma Aβ peptides should be better elucidated with further studies that also compare the accuracy of the different ultrasensitive techniques. Blood NFL is promising as a proxy of neurodegeneration process tout court. Protein misfolding amplification assays can accurately detect α-synuclein in cerebrospinal fluid (CSF), thus representing advancement in the pathologic stratification of AD. In CSF, neurogranin and YKL-40 are further candidate biomarkers tracking synaptic disruption and neuroinflammation, which are additional key pathophysiological pathways related to AD genesis. Advanced statistical analysis using clinical scores and biomarker data to bring together individuals with AD from large heterogeneous cohorts into consistent clusters may promote the discovery of pathophysiological causes and detection of tailored treatments.

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Increased expression of TREM2 in peripheral cells from mild cognitive impairment patients who progress into Alzheimer's disease

Cited by 57 publications

References 36 publications

TREM2 ectodomain and its soluble form in Alzheimer’s disease

TREM2 ectodomain and its soluble form in Alzheimer’s disease

TMEM59 interacts with TREM2 and modulates TREM2-dependent microglial activities

Fluid Candidate Biomarkers for Alzheimer’s Disease: A Precision Medicine Approach

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