title: β2 adrenergic receptor, protein kinase A (PKA) and c-Jun N-terminal kinase (JNK) signaling pathways mediate tau pathology in Alzheimer disease models.
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: Department of Molecular and Integrative Physiology, School of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors: Dayong
authors: D
authors: Wang
authors: Qin
authors: Q
authors: Fu
authors: Yuan
authors: Y
authors: Zhou
authors: Bing
authors: B
authors: Xu
authors: Qian
authors: Q
authors: Shi
authors: Benedict
authors: B
authors: Igwe
authors: Lucas
authors: L
authors: Matt
authors: Johannes W
authors: JW
authors: Hell
authors: Elena V
authors: EV
authors: Wisely
authors: Salvatore
authors: S
authors: Oddo
authors: Yang K
authors: YK
authors: Xiang
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019393:Arrestin / Q000235:genetics / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D049229:Dendritic Spines / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D017397:Prefrontal Cortex / Q000378:metabolism / Q000473:pathology; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D019393:Arrestin; D018343:Receptors, Adrenergic, beta-2; D000071679:Glycogen Synthase Kinase 3 beta; D017868:Cyclic AMP-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D038362:Glycogen Synthase Kinase 3