β2 adrenergic receptor, protein kinase A (PKA) and c-Jun N-terminal kinase (JNK) signaling pathways mediate tau pathology in Alzheimer disease models.

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.

阿尔茨海默病（Alzheimer disease, AD）以伴随tau蛋白过度磷酸化的突触与树突棘丢失为特征的神经退行性病变为核心病理表现。脑内β淀粉样肽（amyloid β peptide, Aβ）的聚集与阿尔茨海默病中由过度磷酸化tau蛋白构成的神经原纤维缠结存在紧密关联。本研究鉴定出β2肾上腺素能受体（β2-adrenergic receptor, β2AR）可介导Aβ诱导的tau病理改变。
在携带早老素1与淀粉样前体蛋白（presenilin 1 and amyloid precursor protein, PS1/APP）家族性人类突变基因的1岁龄转基因小鼠的前额叶皮层（prefrontal cortex, PFC）中，tau蛋白在Ser-214、Ser-262及Thr-181位点的磷酸化水平，以及JNK、GSK3α/β、Ca²⁺/钙调蛋白依赖性蛋白激酶Ⅱ等蛋白激酶的活性均显著升高。
在PS1/APP小鼠中敲除β2AR基因，可大幅降低上述蛋白的磷酸化水平。
进一步分析显示，在原代前额叶皮层神经元中，Aβ通过β2AR-蛋白激酶A（PKA）-JNK通路进行信号转导，该通路介导了tau蛋白在Ser-214与Ser-262位点的绝大多数磷酸化，以及Thr-181位点的部分磷酸化。
Aβ还可诱导β2AR依赖性的抑制蛋白（arrestin）-细胞外调节蛋白激酶1/2（ERK1/2）通路激活，但该通路并不参与tau蛋白的磷酸化过程。不过，抑制ERK1/2的上游激酶丝裂原活化蛋白激酶激酶（MEK）的活性，可部分阻断Aβ诱导的tau蛋白在Thr-181位点的磷酸化。
1岁龄PS1/APP小鼠的前额叶皮层深层树突棘与突触密度降低，且在新物体识别范式中表现出学习记忆功能受损。
敲除β2AR基因可改善上述老年PS1/APP小鼠的病理损伤。
本研究表明，β2AR或可作为预防阿尔茨海默病发生的潜在治疗靶点。