Alzheimer's β-secretase (BACE1) regulates the cAMP/PKA/CREB pathway independently of β-amyloid

Yaomin Chen, Xiumei Huang, Yun wu Zhang, Edward Rockenstein, Guojun D Bu, Todd E. Golde, Eliezer Masliah, Huaxi Xu

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)11390-11395
Number of pages6
JournalJournal of Neuroscience
Volume32
Issue number33
DOIs
StatePublished - Aug 15 2012
Externally publishedYes

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Cyclic AMP Response Element-Binding Protein
Amyloid Precursor Protein Secretases
Cyclic AMP-Dependent Protein Kinases
Amyloid
Enzymes
Serum Amyloid A Protein
Amyloid beta-Protein Precursor
Alzheimer Disease
Phosphorylation
Amyloid Plaques
Memory Disorders
Adenylyl Cyclases
Transgenic Mice
Down-Regulation
Learning

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Alzheimer's β-secretase (BACE1) regulates the cAMP/PKA/CREB pathway independently of β-amyloid. / Chen, Yaomin; Huang, Xiumei; Zhang, Yun wu; Rockenstein, Edward; Bu, Guojun D; Golde, Todd E.; Masliah, Eliezer; Xu, Huaxi.

In: Journal of Neuroscience, Vol. 32, No. 33, 15.08.2012, p. 11390-11395.

Research output: Contribution to journalArticle

Chen, Y, Huang, X, Zhang, YW, Rockenstein, E, Bu, GD, Golde, TE, Masliah, E & Xu, H 2012, 'Alzheimer's β-secretase (BACE1) regulates the cAMP/PKA/CREB pathway independently of β-amyloid', Journal of Neuroscience, vol. 32, no. 33, pp. 11390-11395. https://doi.org/10.1523/JNEUROSCI.0757-12.2012
Chen, Yaomin ; Huang, Xiumei ; Zhang, Yun wu ; Rockenstein, Edward ; Bu, Guojun D ; Golde, Todd E. ; Masliah, Eliezer ; Xu, Huaxi. / Alzheimer's β-secretase (BACE1) regulates the cAMP/PKA/CREB pathway independently of β-amyloid. In: Journal of Neuroscience. 2012 ; Vol. 32, No. 33. pp. 11390-11395.
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