Alzheimer's beta-Secretase (BACE1) Regulates the cAMP/PKA/CREB Pathway Independently of beta-Amyloid
Golde, Todd E.
- 生物医学－已发表论文 
beta-Amyloid protein (A beta), the major component of neuritic plaques in Alzheimer's disease (AD), is derived from proteolytic cleavages of the amyloid precursor protein (APP) by beta-site APP-cleaving enzyme 1 (BACE1) and the gamma-secretase complex. BACE1 is the rate-limiting enzyme for A beta production, and an increase in BACE1 level/activity contributes to the pathogenesis of sporadic AD. In addition to cleaving APP for A beta generation, BACE1 plays multiple physiological roles including the regulation of synaptic functions. Here, we found that overexpression of BACE1 reduces cAMP response element binding protein (CREB) phosphorylation, protein kinase A (PKA) activity, and cAMP levels, whereas downregulation of BACE1 has the opposite effect. We showed that BACE1's effect is independent of its activity for A beta production, which is corroborated by the observation that BACE1 transgenic mice have impaired learning/memory in the absence of neurotoxic human A beta. Furthermore, we demonstrated that BACE1 interacts via its transmembrane domain with adenylate cyclase, resulting in reduction of cellular cAMP levels and thus PKA inactivation and reduced CREB phosphorylation. Our study suggests that in addition to its function as the beta-secretase to produce A beta, BACE1 may contribute to the memory and cognitive deficits typical of AD by regulating the cAMP/PKA/CREB pathway, which is important for memory functions.
CitationJOURNAL OF NEUROSCIENCE,2012,32（33）：11390-11395