Aberrantly activated TAK1 links neuroinflammation and neuronal loss in Alzheimer's disease mouse models. 2023

Kazuhito Sai, and Aoi Nakanishi, and Kimberly M Scofield, and Debra A Tokarz, and Keith E Linder, and Todd J Cohen, and Jun Ninomiya-Tsuji
Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695-7633, USA.

Neuroinflammation is causally associated with Alzheimer's disease (AD) pathology. Reactive glia cells secrete various neurotoxic factors that impair neuronal homeostasis eventually leading to neuronal loss. Although the glial activation mechanism in AD has been relatively well studied, how it perturbs intraneuronal signaling, which ultimately leads to neuronal cell death, remains poorly understood. Here, we report that compound stimulation with the neurotoxic factors TNF and glutamate aberrantly activates neuronal TAK1 (also known as MAP3K7), which promotes the pathogenesis of AD in mouse models. Glutamate-induced Ca2+ influx shifts TNF signaling to hyper-activate TAK1 enzymatic activity through Ca2+/calmodulin-dependent protein kinase II, which leads to necroptotic cellular damage. Genetic ablation and pharmacological inhibition of TAK1 ameliorated AD-associated neuronal loss and cognitive impairment in the AD model mice. Our findings provide a molecular mechanism linking cytokines, Ca2+ signaling and neuronal necroptosis in AD.

UI MeSH Term Description Entries
D002118 Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Coagulation Factor IV,Factor IV,Blood Coagulation Factor IV,Calcium-40,Calcium 40,Factor IV, Coagulation
D000090862 Neuroinflammatory Diseases Diseases characterized by inflammation of the nervous tissue. Neuroinflammation,Neuroinflammatory Disorders,Disease, Neuroinflammatory,Disorder, Neuroinflammatory,Neuroinflammations,Neuroinflammatory Disease,Neuroinflammatory Disorder
D000544 Alzheimer Disease A degenerative disease of the BRAIN characterized by the insidious onset of DEMENTIA. Impairment of MEMORY, judgment, attention span, and problem solving skills are followed by severe APRAXIAS and a global loss of cognitive abilities. The condition primarily occurs after age 60, and is marked pathologically by severe cortical atrophy and the triad of SENILE PLAQUES; NEUROFIBRILLARY TANGLES; and NEUROPIL THREADS. (From Adams et al., Principles of Neurology, 6th ed, pp1049-57) Acute Confusional Senile Dementia,Alzheimer's Diseases,Dementia, Alzheimer Type,Dementia, Senile,Presenile Alzheimer Dementia,Senile Dementia, Alzheimer Type,Alzheimer Dementia,Alzheimer Disease, Early Onset,Alzheimer Disease, Late Onset,Alzheimer Sclerosis,Alzheimer Syndrome,Alzheimer Type Senile Dementia,Alzheimer's Disease,Alzheimer's Disease, Focal Onset,Alzheimer-Type Dementia (ATD),Dementia, Presenile,Dementia, Primary Senile Degenerative,Early Onset Alzheimer Disease,Familial Alzheimer Disease (FAD),Focal Onset Alzheimer's Disease,Late Onset Alzheimer Disease,Primary Senile Degenerative Dementia,Senile Dementia, Acute Confusional,Alzheimer Dementias,Alzheimer Disease, Familial (FAD),Alzheimer Diseases,Alzheimer Type Dementia,Alzheimer Type Dementia (ATD),Alzheimers Diseases,Dementia, Alzheimer,Dementia, Alzheimer-Type (ATD),Familial Alzheimer Diseases (FAD),Presenile Dementia,Sclerosis, Alzheimer,Senile Dementia
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D015398 Signal Transduction The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal
D016207 Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Cytokine
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus

Related Publications

Kazuhito Sai, and Aoi Nakanishi, and Kimberly M Scofield, and Debra A Tokarz, and Keith E Linder, and Todd J Cohen, and Jun Ninomiya-Tsuji
November 2018, Clinical & experimental neuroimmunology,
Kazuhito Sai, and Aoi Nakanishi, and Kimberly M Scofield, and Debra A Tokarz, and Keith E Linder, and Todd J Cohen, and Jun Ninomiya-Tsuji
January 2013, PloS one,
Kazuhito Sai, and Aoi Nakanishi, and Kimberly M Scofield, and Debra A Tokarz, and Keith E Linder, and Todd J Cohen, and Jun Ninomiya-Tsuji
October 2018, Neurobiology of aging,
Kazuhito Sai, and Aoi Nakanishi, and Kimberly M Scofield, and Debra A Tokarz, and Keith E Linder, and Todd J Cohen, and Jun Ninomiya-Tsuji
April 2019, Journal of molecular biology,
Kazuhito Sai, and Aoi Nakanishi, and Kimberly M Scofield, and Debra A Tokarz, and Keith E Linder, and Todd J Cohen, and Jun Ninomiya-Tsuji
September 2017, Oncotarget,
Kazuhito Sai, and Aoi Nakanishi, and Kimberly M Scofield, and Debra A Tokarz, and Keith E Linder, and Todd J Cohen, and Jun Ninomiya-Tsuji
August 2010, International journal of Alzheimer's disease,
Kazuhito Sai, and Aoi Nakanishi, and Kimberly M Scofield, and Debra A Tokarz, and Keith E Linder, and Todd J Cohen, and Jun Ninomiya-Tsuji
August 2007, The Journal of experimental medicine,
Kazuhito Sai, and Aoi Nakanishi, and Kimberly M Scofield, and Debra A Tokarz, and Keith E Linder, and Todd J Cohen, and Jun Ninomiya-Tsuji
January 2021, Journal of Alzheimer's disease : JAD,
Kazuhito Sai, and Aoi Nakanishi, and Kimberly M Scofield, and Debra A Tokarz, and Keith E Linder, and Todd J Cohen, and Jun Ninomiya-Tsuji
April 1998, Aging (Milan, Italy),
Kazuhito Sai, and Aoi Nakanishi, and Kimberly M Scofield, and Debra A Tokarz, and Keith E Linder, and Todd J Cohen, and Jun Ninomiya-Tsuji
October 2020, International journal of molecular sciences,
Copied contents to your clipboard!