2024 article
The Mechanism and Roles of TAK1 hyperactivation in the Alzheimer's Disease Mouse Model
Nakanishi-Hester, A., Sai, K., & Ninomiya-Tsuji, J. (2024, March). JOURNAL OF BIOLOGICAL CHEMISTRY, Vol. 300, pp. S556–S556.
open access via www.jbc.org (publisher PDF)
Source: Web Of Science
Added: December 2, 2024
Neuroinflammation in the hippocampus is causally associated with Alzheimer's Disease (AD). However, the precise mechanisms of how inflammatory signaling in each cell type, neuron, oligodendrocyte, astrocyte, microglia, etc. impacts neuronal function remain elusive. Oligodendrocytes (OLGs), known for myelin formation and neuron support, emerge as potential contributors to chronic neuroinflammation. Unlike neurons, OLGs can regenerate throughout the lifespan, making them viable targets for understanding and potentially mitigating AD. We found that mitogen-activated protein kinase kinase kinase 7 (MAP3K7), also known as TAK1, a central player in intracellular inflammation signaling, is hyperactivated in the hippocampus of aged and AD model mice. We previously demonstrated that neuron lineage specific Tak1 gene deletion ameliorated neuron loss and cognitive impairment. These results suggest that TAK1-driven inflammatory signaling promotes AD. In our current study, my objectives are to elucidate the mechanism of TAK1 hyperactivation and its role, particularly, in OLGs. We found that compound stimulation of an inflammatory cytokine, TNF and a neurotransmitter glutamate-calcium influx activates TAK1. In addition, calcium calmodulin kinase II (CaMKII) is found to be involved in TAK1 activation by binding to and modulates TAK1 binding protein 2, TAB2. TAB2 serves a dual role in the regulation of TAK1 as it can recruit activators and deactivators of TAK1 and deleting Tab2 gene hyperactivates TAK1. These results collectively suggest that calcium-CaMKII-TAB2 blockade together with TNF hyperactivates TAK1. We are currently analyzing mice with OLG-specific Tab2 deletion (TAK1 hyper-activation). We found that Tab2 deletion blocks OLG differentiation, suggesting that TAK1 hyperactivation impairs OLG-derived support for neurons. Our results uncovered the importance of TAK1 in AD pathogenesis, offering potential avenues for therapeutic intervention. The study is funded by National Institute of Health, R35GM139601, 2019-AARG-NTF-641347.