Objective: this study explored whether TREM2 plays a protective role in PD with cognitive impairment by promoting the activation of DAM.

Background: The latest research found that anti-inflammaory disease-associated microglia (DAM), regulated by TREM2-dependent, plays a protective role in a variety of neurodegenerative disease.

Method: Adenovirus and lentivirus was used to silence the expression of TREM2 protein in 4-month-old A53T α-Syn PD mice and BV2 microglia. The cognitive status of mice was evaluated by Morris water maze and new object recognition; α- Synuclein（α- Syn）aggregation, microglial activation and expression of inflammatory cytokines, core markers of DAM, MAPK and NF- κB pathway protein were evaluated by Western blot, immunofluorescence, immunohistochemistry and qPCR. The culture medium after PFF stimulation of BV2 microglia in each group was further used to stimulate HT22 neurons, CCK8 and flow cytometry were used to detect cell viability and apoptosis.

Results: (1) After silencing the expression of TREM2 in hippocampus or BV2, The expression of synaptic protein (PSD95) and neuronal marker NeuN in A53T α-Syn PD mice decreased without change of α- Syn protein, and cognitive impairment of A53T α-Syn PD mice were aggravated; The expression of Iba1, and inflammatory cytokines (iNOS, COX2 protein and TNF-α、 IL-1β、 IL-6 mRNA) were significantly increased; The expression of the core marker of DAM, such as, Itgax protein, and the mRNA of Itgax, APOE, Timp2, Clec7a, CD68, Lpl, Axl, Ctsl, CCL6 and other genes were decreased significantly, and the expression of P-JNK, P-ERK in MAPK pathway and P-P65 in NF-κB pathway were significantly increased; The culture medium after PFF stimulation of microglia was used to stimulate HT22 neurons, and the activity of neurons were decreased and cell apoptosis was increased;

(2) The core marker of DAM, Itgax protein, decreased due to the TREM2 silencing, was increased significantly after the inhibition of ERK1/2 signal pathway.

Conclusion: The results of this study suggest that in α-Syn-induced neuroinflammation, TREM2 may promote the activation of anti-inflammatory DAM through the ERR1/2 signal pathway, thereby inhibiting neuroinflammation, reducing neuronal damage in the hippocampus, and plays a protective role in PD with cognitive impairment.

« Back to 2023 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/protective-effect-and-mechanism-of-trem2-in-parkinsons-disease-with-cognitive-impairment/