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β2 adrenergic receptor, protein kinase A (PKA) and c-Jun N-terminal kinase (JNK) signaling pathways mediate tau pathology in Alzheimer disease models.
J Biol Chem. 2013 Apr 12; 288(15):10298-307.JB

Abstract

Alzheimer disease (AD) is characterized by neurodegeneration marked by loss of synapses and spines associated with hyperphosphorylation of tau protein. Accumulating amyloid β peptide (Aβ) in brain is linked to neurofibrillary tangles composed of hyperphosphorylated tau in AD. Here, we identify β2-adrenergic receptor (β2AR) that mediates Aβ-induced tau pathology. In the prefrontal cortex (PFC) of 1-year-old transgenic mice with human familial mutant genes of presenilin 1 and amyloid precursor protein (PS1/APP), the phosphorylation of tau at Ser-214 Ser-262 and Thr-181, and the protein kinases including JNK, GSK3α/β, and Ca(2+)/calmodulin-dependent protein kinase II is increased significantly. Deletion of the β2AR gene in PS1/APP mice greatly decreases the phosphorylation of these proteins. Further analysis reveals that in primary PFC neurons, Aβ signals through a β2AR-PKA-JNK pathway, which is responsible for most of the phosphorylation of tau at Ser-214 and Ser-262 and a significant portion of phosphorylation at Thr-181. Aβ also induces a β2AR-dependent arrestin-ERK1/2 activity that does not participate in phosphorylation of tau. However, inhibition of the activity of MEK, an upstream enzyme of ERK1/2, partially blocks Aβ-induced tau phosphorylation at Thr-181. The density of dendritic spines and synapses is decreased in the deep layer of the PFC of 1-year-old PS1/APP mice, and the mice exhibit impairment of learning and memory in a novel object recognition paradigm. Deletion of the β2AR gene ameliorates pathological effects in these senile PS1/APP mice. The study indicates that β2AR may represent a potential therapeutic target for preventing the development of AD.

Authors+Show Affiliations

Department of Molecular and Integrative Physiology, School of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23430246

Citation

Wang, Dayong, et al. "Β2 Adrenergic Receptor, Protein Kinase a (PKA) and c-Jun N-terminal Kinase (JNK) Signaling Pathways Mediate Tau Pathology in Alzheimer Disease Models." The Journal of Biological Chemistry, vol. 288, no. 15, 2013, pp. 10298-307.
Wang D, Fu Q, Zhou Y, et al. Β2 adrenergic receptor, protein kinase A (PKA) and c-Jun N-terminal kinase (JNK) signaling pathways mediate tau pathology in Alzheimer disease models. J Biol Chem. 2013;288(15):10298-307.
Wang, D., Fu, Q., Zhou, Y., Xu, B., Shi, Q., Igwe, B., Matt, L., Hell, J. W., Wisely, E. V., Oddo, S., & Xiang, Y. K. (2013). Β2 adrenergic receptor, protein kinase A (PKA) and c-Jun N-terminal kinase (JNK) signaling pathways mediate tau pathology in Alzheimer disease models. The Journal of Biological Chemistry, 288(15), 10298-307. https://doi.org/10.1074/jbc.M112.415141
Wang D, et al. Β2 Adrenergic Receptor, Protein Kinase a (PKA) and c-Jun N-terminal Kinase (JNK) Signaling Pathways Mediate Tau Pathology in Alzheimer Disease Models. J Biol Chem. 2013 Apr 12;288(15):10298-307. PubMed PMID: 23430246.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - β2 adrenergic receptor, protein kinase A (PKA) and c-Jun N-terminal kinase (JNK) signaling pathways mediate tau pathology in Alzheimer disease models. AU - Wang,Dayong, AU - Fu,Qin, AU - Zhou,Yuan, AU - Xu,Bing, AU - Shi,Qian, AU - Igwe,Benedict, AU - Matt,Lucas, AU - Hell,Johannes W, AU - Wisely,Elena V, AU - Oddo,Salvatore, AU - Xiang,Yang K, Y1 - 2013/02/19/ PY - 2013/2/23/entrez PY - 2013/2/23/pubmed PY - 2013/6/8/medline SP - 10298 EP - 307 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 288 IS - 15 N2 - Alzheimer disease (AD) is characterized by neurodegeneration marked by loss of synapses and spines associated with hyperphosphorylation of tau protein. Accumulating amyloid β peptide (Aβ) in brain is linked to neurofibrillary tangles composed of hyperphosphorylated tau in AD. Here, we identify β2-adrenergic receptor (β2AR) that mediates Aβ-induced tau pathology. In the prefrontal cortex (PFC) of 1-year-old transgenic mice with human familial mutant genes of presenilin 1 and amyloid precursor protein (PS1/APP), the phosphorylation of tau at Ser-214 Ser-262 and Thr-181, and the protein kinases including JNK, GSK3α/β, and Ca(2+)/calmodulin-dependent protein kinase II is increased significantly. Deletion of the β2AR gene in PS1/APP mice greatly decreases the phosphorylation of these proteins. Further analysis reveals that in primary PFC neurons, Aβ signals through a β2AR-PKA-JNK pathway, which is responsible for most of the phosphorylation of tau at Ser-214 and Ser-262 and a significant portion of phosphorylation at Thr-181. Aβ also induces a β2AR-dependent arrestin-ERK1/2 activity that does not participate in phosphorylation of tau. However, inhibition of the activity of MEK, an upstream enzyme of ERK1/2, partially blocks Aβ-induced tau phosphorylation at Thr-181. The density of dendritic spines and synapses is decreased in the deep layer of the PFC of 1-year-old PS1/APP mice, and the mice exhibit impairment of learning and memory in a novel object recognition paradigm. Deletion of the β2AR gene ameliorates pathological effects in these senile PS1/APP mice. The study indicates that β2AR may represent a potential therapeutic target for preventing the development of AD. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/23430246/β2_adrenergic_receptor_protein_kinase_A__PKA__and_c_Jun_N_terminal_kinase__JNK__signaling_pathways_mediate_tau_pathology_in_Alzheimer_disease_models_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=23430246 DB - PRIME DP - Unbound Medicine ER -