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TonEBP Haploinsufficiency Attenuates Microglial Activation and Memory Deficits in Middle-Aged and Amyloid β
Jong Youl Lee1,2, Eun Ae Jeong1, Jaewoong Lee1
1Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea.
Abstract:
Age-related microglial activation is associated with cognitive impairment. Tonicity-responsive enhancer-binding protein (TonEBP) is a critical mediator of microglial activation in response to neuroinflammation. However, the precise role of TonEBP in the middle-aged brain is not yet known. We used TonEBP haploinsufficient mice to investigate the role of TonEBP in middle-aged or amyloid β oligomer (AβO)-injected brains and examined the effect of TonEBP knockdown on AβO-treated BV2 microglial cells. Consistent with an increase in microglial activation with aging, hippocampal TonEBP expression levels were increased in middle-aged (12-month-old) and old (24-month-old) mice compared with young (6-month-old) mice. Middle-aged TonEBP haploinsufficient mice showed reduced microglial activation and fewer memory deficits than wild-type mice. Electron microscopy revealed that synaptic pruning by microglial processes was reduced by TonEBP haploinsufficiency. TonEBP haploinsufficiency also reduced dendritic spine loss and improved memory deficits in AβO-treated mice. Furthermore, TonEBP knockdown attenuated migration and phagocytosis in AβO-treated BV2 cells. These findings suggest that TonEBP plays important roles in age-related microglial activation and memory deficits.
Insights
Tonicity-responsive enhancer-binding protein (TonEBP) drives age-related microglial activation and memory loss. Reducing TonEBP in middle-aged mice improved cognitive function and reduced neuroinflammation.
Area of Science:
- Neuroscience
- Immunology
- Aging Research
Background:
- Microglial activation increases with age and is linked to cognitive decline.
- Tonicity-responsive enhancer-binding protein (TonEBP) mediates microglial responses to neuroinflammation.
- The role of TonEBP in the aging brain remains unclear.
Purpose of the Study:
- To investigate the role of TonEBP in age-related microglial activation and memory deficits.
- To examine the impact of TonEBP haploinsufficiency on the middle-aged brain.
- To assess the effect of TonEBP knockdown on amyloid-beta oligomer (AβO)-treated microglial cells.
Main Methods:
- Utilized TonEBP haploinsufficient mice of varying ages (6, 12, and 24 months).
- Administered amyloid-beta oligomers (AβO) to middle-aged mice and BV2 microglial cells.
- Performed electron microscopy to analyze synaptic structures.
- Assessed microglial activation, memory function, cell migration, and phagocytosis.
Main Results:
- Hippocampal TonEBP expression increased with age.
- TonEBP haploinsufficiency reduced microglial activation and memory deficits in middle-aged mice.
- Synaptic pruning, dendritic spine loss, and memory impairments were ameliorated by reducing TonEBP in AβO-treated mice.
- TonEBP knockdown decreased migration and phagocytosis in AβO-treated BV2 cells.
Conclusions:
- TonEBP is a key mediator of age-related microglial activation.
- TonEBP contributes to memory deficits associated with aging and neuroinflammation.
- Targeting TonEBP may offer a therapeutic strategy for age-related cognitive impairment.
