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Gene-environment Interaction Models to Unmask Susceptibility Mechanisms in Parkinson's Disease
Published on: January 7, 2014
TREM2 deficiency aggravates neuroinflammatory response and cognitive impairment via disease-associated microglia in
Zhang Piao1, Zhu Baoyu1, Feng Jiezhu2
1Department of Neurology, Guangdong Neuroscience Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong Province, 510080, China; Guangzhou Key Laboratory of Diagnosis and Treatment for Neurodegenerative Diseases, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Guangzhou, 510080, China.
Abstract:
This study explores whether Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) regulates the distinct disease-related microglia (DAM) phenotype and exerts a protective role in cognitive impairment in Parkinson's disease (PD). Adeno-associated virus carrying TREM2 shRNA (AAV-TREM2-shRNA) was injected into the bilateral hippocampus of the A53T α-Synuclein (α-Syn) transgenic PD mouse model; Additionally, lentivirus was transduced into BV2 microglial cells to knock out the expression of TREM2, which were subsequently stimulated with α-Syn preformed fibrils (PFF). Furthermore, cognitive status of mice, α-Syn aggregation, microglia status, expression of inflammatory factors, pro-inflammatory and anti-inflammatory DAM markers, MAPK and NF- κB pathway activation status and neuron apoptosis were evaluated. TREM2 deficiency induced cognitive impairment in A53T α-Syn PD mice by decreased performance in the novel objective recognition and Morris water maze tests. TREM2 knockdown resulted in synaptic loss, microglial activation, increased inflammatory factors, and MAPK and NF- κB pathway activation in the hippocampus of mice. In vitro, TREM2 deficiency exacerbated the inflammatory response of BV2 cells stimulated by α-Syn PFF by inhibiting anti-inflammatory DAM, and promoting neuronal apoptosis and Ser129-phosphorylation of α-Syn. TREM2 knockdown also promoted pro-inflammatory DAM activation and increased inflammatory factors expression via the ERK1/2 signaling pathway. Our findings suggest that TREM2 plays a protective role in cognitive impairment and promotes anti-inflammatory DAM activation via the ERK1/2 signaling pathway in PD mice, providing novel insight into the immunopathogenesis of cognitive impairments in PD.
Insights
Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) deficiency worsens cognitive impairment in Parkinson's disease (PD) models. TREM2 promotes anti-inflammatory microglia activation, offering a protective role against PD-related cognitive decline.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and cognitive impairments.
- Microglia, the resident immune cells of the brain, play a complex role in PD pathogenesis.
- Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is a microglial receptor implicated in neuroinflammation and neurodegeneration.
Purpose of the Study:
- To investigate the role of TREM2 in regulating disease-associated microglia (DAM) phenotype.
- To determine if TREM2 exerts a protective effect against cognitive impairment in a PD mouse model.
- To elucidate the molecular mechanisms underlying TREM2's function in PD-related cognitive decline.
Main Methods:
- Adeno-associated virus (AAV)-mediated TREM2 knockdown in the hippocampus of A53T α-Synuclein transgenic PD mice.
- Lentiviral TREM2 knockout in BV2 microglial cells stimulated with α-Syn preformed fibrils (PFFs).
- Evaluation of cognitive function, α-Syn aggregation, microglial activation, inflammatory markers, and signaling pathways (MAPK, NF-κB, ERK1/2).
Main Results:
- TREM2 deficiency significantly impaired cognitive performance in PD mice, evidenced by deficits in novel object recognition and Morris water maze tests.
- TREM2 knockdown led to synaptic loss, increased microglial activation, elevated inflammatory factors, and enhanced MAPK and NF-κB pathway activation in the hippocampus.
- In vitro, TREM2 deficiency exacerbated α-Syn PFF-induced inflammation, inhibited anti-inflammatory DAM, promoted neuronal apoptosis, and increased α-Syn phosphorylation via the ERK1/2 pathway.
Conclusions:
- TREM2 plays a crucial protective role in mitigating cognitive impairment in Parkinson's disease.
- TREM2 promotes anti-inflammatory DAM activation, likely through the ERK1/2 signaling pathway.
- These findings offer novel insights into the immunopathogenesis of cognitive dysfunction in PD and highlight TREM2 as a potential therapeutic target.
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