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.
Highlights
Accumulating evidence indicates that  receptors (AR) may be involved in Alzheimer disease (AD) pathology and that amyloid  peptide (A) may interact with 2AR independently of presynaptic activities
We found that the phosphorylation of tau at Ser-214, Ser-262, and Thr-181 was increased in the prefrontal cortex (PFC) of 6-month-old and 1-year-old presenilin 1 and amyloid precursor protein (PS1/APP) mice compared with wild-type mice (Fig. 1, A–C, and data not shown)
The A-induced tau phosphorylation was not affected by the exchange protein activated by cAMP (Epac) inhibitor brefeldin A (10Ϫ7 M), and treating the cells with the Epac-selective activator 8-CPT-2Me-cAMP (10Ϫ7 M) for 5 min did not induce tau phosphorylation (Fig. 3, H and I). These results indicate that tau phosphorylation at Ser-214 and Ser-262 is primarily dependent on 2AR-adenylyl cyclase-PKA signaling
Summary
Accumulating evidence indicates that  receptors (AR) may be involved in Alzheimer disease (AD) pathology and that amyloid  peptide (A) may interact with 2AR independently of presynaptic activities. Results: 2AR, PKA, and JNK mediate A-induced phosphorylation of tau in vivo and in vitro. Significance: This work indicates a potential mechanism for altering AD pathology by blocking 2ARs. Alzheimer disease (AD) is characterized by neurodegeneration marked by loss of synapses and spines associated with hyperphosphorylation of tau protein. 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, GSK3␣/, and Ca2؉/calmodulin-dependent protein kinase II is increased significantly. Further analysis reveals that in primary PFC neurons, A signals through a 2AR-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 Thr181. The study indicates that 2AR may represent a potential therapeutic target for preventing the development of AD
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