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Role of Vitamin D and Antioxidant Functional Foods in the Prevention and Treatment of Alzheimer’s Disease Pathology
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
In patients with AD, overactivation of microglial cells and astrocytes are associated with neuroinflammation and disease progression. In the initial phase of the disease, astrocytes are activated and increased glial fibrillary acidic protein (GFAP)‑positive astrocytes can be observed with Aβ deposition around blood cells. As the disease progresses in animal models, astrocyte atrophy with decreased dendritic branching and volume contraction can be observed (Chen & Mobley, 2019). There is increasing evidence that microglial activity can not only protect against AD progression via TREM2 (triggering receptor expressed in myeloid cells 2) but can also affect neuronal viability. Additionally, TREM2 mutations also appear to have an impact on the ability of microglia to phagocytize Aβ (Mammana et al., 2018). Microglia impacts synaptic loss and can secrete inflammatory mediators that impact tau pathology (Hansen, Hanson, & Sheng, 2018). Aβ oligomers and fibrils can modulate microglial activation via multiple receptors that can result in the production of proinflammatory cytokines such as IL-1, IL-6, and TNF-a that cause a cyclic increase in inflammation (Marttinen et al., 2018). With disease progression, the microglia that is in the proximity of plaques appears to be less ramified with noted decreases in arborizations and evidence of dystrophic changes. In addition to these morphological alterations, there is a change in microglial receptor expression (Franco-Bocanegra, McAuley, Nicoll, & Boche, 2019).
Hyperkinetic Movement Disorders
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Morales-Briceno Hugo, Victor S.C. Fung, Annu Aggarwal, Philip Thompson
Frontotemporal dementia (FTD) associated with chorea: TARDBP mutations.UBQLN2 mutations.VCP mutations.TREM2 mutations.
Epigenetic Alterations in Alzheimer’s Disease and Its Therapeutic and Dietary Interventions
Published in Atanu Bhattacharjee, Akula Ramakrishna, Magisetty Obulesu, Phytomedicine and Alzheimer’s Disease, 2020
P. M. Aswathy, C. M. Shafeeque, Moinak Banerjee
Recently, several genome-wide association studies have revealed Triggering Receptor Expressed on Myeloid cells 2 (TREM2) to be a susceptibility gene associated with AD and other neurodegenerative diseases. TREM2 expression was upregulated in the hippocampus of AD patients compared with controls and 5hmC was shown to play a role in the regulation of TREM2 expression (Celarain et al. 2016). In the AD brain, increased DNA methylation in the superior temporal gyrus at a CpG site located 289 bp upstream of the transcription start site of the TREM2 gene was reported in three independent study cohorts, and a meta-analysis across all three cohorts revealed a consistent AD-associated hypermethylation (Smith et al. 2016). Furthermore, hypomethylation at intron 1 showed higher TREM2 mRNA expression in the peripheral leukocytes of AD subjects relative to controls (Ozaki et al. 2017). All these reports point toward TREM2 serving as an epigenetically altered biomarker for predicting AD.
Elevated sTREM2 and NFL levels in patients with sepsis associated encephalopathy
Published in International Journal of Neuroscience, 2023
Günseli Orhun, Figen Esen, Vuslat Yilmaz, Canan Ulusoy, Elif Şanlı, Elif Yıldırım, Hakan Gürvit, Perihan Ergin Özcan, Serra Sencer, Nerses Bebek, Erdem Tüzün
Dysfunction of triggering receptor expressed on myeloid cells 2 (TREM2), which is expressed by microglia in the brain and regulates microglial phagocytosis, has been implicated in mild cognitive impairment (MCI), Alzheimer disease, frontotemporal dementia and HIV-associated neurocognitive disorders [15–17]. Animal studies suggest that microglial TREM2 has a dual function in the brain. While TREM2 activity may have a neuroprotective action through increased elimination of amyloid deposits, it may also accelerate cognitive dysfunction through the facilitation of synaptic loss [18]. Peripheral blood expression levels of TREM2 are increased during the transition from normal cognition to MCI and dementia in line with the progression of hippocampal atrophy, thus suggesting that CSF and serum levels of soluble TREM2 (sTREM2) may potentially serve as a prognostic biomarker of cognitive decline in neurological disorders [19, 20].
Discovery and engineering of an anti-TREM2 antibody to promote amyloid plaque clearance by microglia in 5XFAD mice
Published in mAbs, 2022
Peng Zhao, Yuanzhong Xu, Xuejun Fan, Leike Li, Xin Li, Hisashi Arase, Qingchun Tong, Ningyan Zhang, Zhiqiang An
TREM2 has been shown to play key roles in microglia clusters surrounding plaques and the subsequent removal of plaques.13 We collected the brains from the treated mice after perfusion. Floating slices were stained with the 6E10 antibody to label Aβ plaques. We used a human IBA1-specific antibody and a human TREM2-specific-antibody to label human microglia. As shown in Figure 5b,c, the IBA1 area within 30 µm of plaques was 135.8 ± 9.29 µm2 in the Ab2 TVD-Ig/αTfR treated mice, which represents a significant increase of sevenfold over mice treated with Ab2 TVD-Ig/Ctrl (IBA area = 17.13 ± 3.06 µm2) or Ctrl/αTfR (IBA area = 19.34 ± 5.27 µm2), indicating that the tetravalent Ab2 TVD-Ig/αTfR bispecific antibody significantly increased microglia clustering surrounding the plaques. This observation is consistent with our in vitro cell-based results showing that Ab2-mediated TREM2 activation promotes microglia migration toward the oAβ-lipid complex. We observed significant co-localization of IBA1 and TREM2 staining (Figure 5b), which indicates the expression of TREM2 in hMGLs. This finding is consistent with the previous report that TREM2 is expressed in microglia.13
Cerebrospinal fluid and blood biomarkers for neurodegenerative dementias: An update of the Consensus of the Task Force on Biological Markers in Psychiatry of the World Federation of Societies of Biological Psychiatry
Published in The World Journal of Biological Psychiatry, 2018
Piotr Lewczuk, Peter Riederer, Sid E. O’Bryant, Marcel M. Verbeek, Bruno Dubois, Pieter Jelle Visser, Kurt A. Jellinger, Sebastiaan Engelborghs, Alfredo Ramirez, Lucilla Parnetti, Clifford R. Jack, Charlotte E. Teunissen, Harald Hampel, Alberto Lleó, Frank Jessen, Lidia Glodzik, Mony J. de Leon, Anne M. Fagan, José Luis Molinuevo, Willemijn J. Jansen, Bengt Winblad, Leslie M. Shaw, Ulf Andreasson, Markus Otto, Brit Mollenhauer, Jens Wiltfang, Martin R. Turner, Inga Zerr, Ron Handels, Alexander G. Thompson, Gunilla Johansson, Natalia Ermann, John Q. Trojanowski, Ilker Karaca, Holger Wagner, Patrick Oeckl, Linda van Waalwijk van Doorn, Maria Bjerke, Dimitrios Kapogiannis, H. Bea Kuiperij, Lucia Farotti, Yi Li, Brian A. Gordon, Stéphane Epelbaum, Stephanie J. B. Vos, Catharina J. M. Klijn, William E. Van Nostrand, Carolina Minguillon, Matthias Schmitz, Carla Gallo, Andrea Lopez Mato, Florence Thibaut, Simone Lista, Daniel Alcolea, Henrik Zetterberg, Kaj Blennow, Johannes Kornhuber
In the CNS, the triggering receptor expressed on myeloid cells 2 (TREM2) is specifically expressed on microglia as a transmembrane protein that is processed by α- and γ-secretases (Colonna and Wang 2016). TREM2 mutations cause neurodegenerative diseases and were recently linked to AD (Guerreiro et al. 2013; Jonsson et al. 2013). The ectodomain is shed into the CSF in response to microglial activation (sTREM2) and was first measured in CSF from MS patients, who had increased concentrations as compared to controls. Increased CSF sTREM2 concentrations were recently reported in both dementia and MCI stages of AD and CSF sTREM2 correlate with CSF Tau but not CSF Aβ42 concentrations, suggesting that microglial activation occurs in close connection with onset of neurodegeneration (Heslegrave et al. 2016; Piccio et al. 2016; Suarez-Calvet et al. 2016). The association of CSF sTREM2 with protective versus harmful microglial activation is presently unknown; longitudinal studies with repeated CSF samplings over time are needed to determine this.