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Article type: Research Article
Authors: Stoiljkovic, Milana; b; * | Gutierrez, Karel Oteroc | Kelley, Craigd | Horvath, Tamas L.a | Hajós, Mihálya; e
Affiliations: [a] Department of Comparative Medicine, Yale School of Medicine, Yale University, New Haven, CT, USA | [b] Department of Pharmacology, School of Medicine, University of Nis, Nis, Serbia | [c] Department of Neuroimmunology, Acute Neurology and Pain, Biogen Inc., Cambridge, MA, USA | [d] Joint Biomedical Engineering Program, The State University of New York-Downstate and New York University-Tandon, Brooklyn, NY, USA | [e] Cognito Therapeutics, Cambridge, MA, USA
Correspondence: [*] Correspondence to: Milan Stoiljkovic, MD, PhD, Department of Comparative Medicine, Yale University School of Medicine, 310 Cedar St, New Haven, CT 06520, USA. Tel.: +1 203 785 2525; Fax: +1 203 785 7499; E-mail: [email protected].
Abstract: Background:Genetic mutations in triggering receptor expressed on myeloid cells-2 (TREM2) have been strongly associated with increased risk of developing Alzheimer’s disease (AD) and other progressive dementias. In the brain, TREM2 protein is specifically expressed on microglia suggesting their active involvement in driving disease pathology. Using various transgenic AD models to interfere with microglial function through TREM2, several recent studies provided important data indicating a causal link between TREM2 and underlying amyloid-β (Aβ) and tau pathology. However, mechanisms by which TREM2 contributes to increased predisposition to clinical AD and influences its progression still remain largely unknown. Objective:Our aim was to elucidate the potential contribution of TREM2 on specific oscillatory dynamic changes associated with AD pathophysiology. Methods:Spontaneous and brainstem nucleus pontis oralis stimulation-induced hippocampal oscillation paradigm was used to investigate the impact of TREM2 haploinsufficiency TREM2(Het) or total deficiency TREM2(Hom) on hippocampal network function in wild-type and Aβ overproducing Tg2576 mice under urethane anesthesia. Results:Partial (TREM2(Het)) or total (TREM2(Hom)) deletion of TREM2 led to increased incidence of spontaneous epileptiform seizures in both wild-type and Tg2576 mice. Importantly, deficiency of TREM2 in Tg2576 mice significantly diminished power of theta oscillation in the hippocampus elicited by brainstem-stimulation compared to wild-type mice. However, it did not affect hippocampal theta-phase gamma-amplitude coupling significantly, since over a 60%reduction was found in coupling in Tg2576 mice regardless of TREM2 function. Conclusion:Our findings indicate a role for TREM2-dependent microglial function in the hippocampal neuronal excitability in both wild type and Aβ overproducing mice, whereas deficiency in TREM2 function exacerbates disruptive effects of Aβ on hippocampal network oscillations.
Keywords: Alzheimer’s disease, hippocampus, microglia, theta oscillation, seizure, TREM2
DOI: 10.3233/JAD-210041
Journal: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 837-847, 2022
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