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- Title
Alzheimer's β-Secretase (BACE1) Regulates the cAMP/PKA/ CREB Pathway Independently of β-Amyloid.
- Authors
Yaomin Chen; Xiumei Huang; Yun-wu Zhang; Rockenstein, Edward; Guojun Bu; Golde, Todd E.; Masliah, Eliezer; Huaxi Xu
- Abstract
β-Amyloid protein (Aβ), the major component of neuritic plaques in Alzheimer's disease (AD), is derived from proteolytic cleavages of the amyloid precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and the γ-secretase complex. BACE1 is the rate-limiting enzyme for Aβ production, and an increase in BACE1 level/activity contributes to the pathogenesis of sporadic AD. In addition to cleaving APP for Aβ 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 Aβ production, which is corroborated by the observation that BACE1 transgenic mice have impaired learning/memory in the absence of neurotoxic human Aβ. 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 β-secretase to produce Aβ, 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.
- Subjects
AMYLOID beta-protein; ALZHEIMER'S disease; AMYLOID beta-protein precursor; NEUROTOXIC agents; GLYCOPROTEINS; PHOSPHORYLATION; PROTEIN kinases
- Publication
Journal of Neuroscience, 2012, Vol 32, Issue 33, p11390
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.0757-12.2012