Pharmacy Practice Faculty Publications

Title

β-Amyloid-(1–42) Impairs Activity-dependent cAMP-response Element-binding Protein Signaling in Neurons at Concentrations in Which Cell Survival Is Not Compromised

Document Type

Article

Publication Date

5-18-2001

Journal Title

The Journal of Biological Chemistry

ISSN

0021-9258

Volume

276

Issue

20

First Page

17301

Last Page

17306

DOI

http://dx.doi.org/10.1074/jbc.m010450200

PubMed ID

11278679

Abstract

Cognitive impairment is a major feature of Alzheimer's disease and is accompanied by β-amyloid (Aβ) deposition. Transgenic animal models that overexpress Aβ exhibit learning and memory impairments, but neuronal degeneration is not a consistent characteristic. We report that levels of Aβ-(1–42), which do not compromise the survival of cortical neurons, may indeed interfere with functions critical for neuronal plasticity. Pretreatment with Aβ-(1–42), at sublethal concentrations, resulted in a suppression of cAMP-response element-binding protein (CREB) phosphorylation, induced by exposure to either 30 mM KCl or 10 μM N-methyl-D-aspartate. The effects of Aβ-(1–42) seem to involve mechanisms unrelated to degenerative changes, since Aβ-(25–35), a toxic fragment of Aβ, at sublethal concentrations did not interfere with activity-dependent CREB phosphorylation. Furthermore, caspase inhibitors failed to counteract the Aβ-(1–42)-evoked suppression of CREB activation. Aβ-(1–42) also interfered with events downstream of activated CREB. The Aβ-(1–42) treatment suppressed the activation of the cAMP response element-containing brain-derived neurotrophic factor (BDNF) exon III promoter and the expression of BDNF exon IIII mRNA induced by neuronal depolarization. In view of the critical role of CREB and BDNF in neuronal plasticity, including learning and memory, the observations indicate a novel pathway through which Aβ may interfere with neuronal functions and contribute to cognitive deficit in Alzheimer's disease before the stage of massive neuronal degeneration.

Keywords

Alzheimer's disease, learning, memory, β-amyloid, neuronal plasticity, neuronal degeneration, cyclic AMP response