PMID- 11278679
OWN - NLM
STAT- MEDLINE
DCOM- 20010705
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 276
IP  - 20
DP  - 2001 May 18
TI  - Beta -amyloid-(1-42) impairs activity-dependent cAMP-response element-binding 
      protein signaling in neurons at concentrations in which cell survival Is not 
      compromised.
PG  - 17301-6
AB  - Cognitive impairment is a major feature of Alzheimer's disease and is accompanied 
      by beta-amyloid (Abeta) deposition. Transgenic animal models that overexpress 
      Abeta exhibit learning and memory impairments, but neuronal degeneration is not a 
      consistent characteristic. We report that levels of Abeta-(1-42), which do not 
      compromise the survival of cortical neurons, may indeed interfere with functions 
      critical for neuronal plasticity. Pretreatment with Abeta-(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 
      microm N-methyl-d-aspartate. The effects of Abeta-(1-42) seem to involve 
      mechanisms unrelated to degenerative changes, since Abeta-(25-35), a toxic 
      fragment of Abeta, at sublethal concentrations did not interfere with 
      activity-dependent CREB phosphorylation. Furthermore, caspase inhibitors failed 
      to counteract the Abeta-(1-42)-evoked suppression of CREB activation. 
      Abeta-(1-42) also interfered with events downstream of activated CREB. The 
      Abeta-(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 Abeta may 
      interfere with neuronal functions and contribute to cognitive deficit in 
      Alzheimer's disease before the stage of massive neuronal degeneration.
FAU - Tong, L
AU  - Tong L
AD  - University of California, Irvine Institute for Brain Aging and Dementia, Irvine, 
      California 92697-4540, USA. tongl@uci.edu
FAU - Thornton, P L
AU  - Thornton PL
FAU - Balazs, R
AU  - Balazs R
FAU - Cotman, C W
AU  - Cotman CW
LA  - eng
GR  - R01-NS-40953/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20010226
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Amino Acid Chloromethyl Ketones)
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 0 (Cysteine Proteinase Inhibitors)
RN  - 0 (Peptide Fragments)
RN  - 0 (RNA, Messenger)
RN  - 0 (amyloid beta-protein (1-42))
RN  - 0 (amyloid beta-protein (25-35))
RN  - 0 (benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone)
RN  - 6384-92-5 (N-Methylaspartate)
RN  - 660YQ98I10 (Potassium Chloride)
SB  - IM
MH  - Amino Acid Chloromethyl Ketones/pharmacology
MH  - Amyloid beta-Peptides/*pharmacology
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/*genetics
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Cerebral Cortex/cytology/physiology
MH  - Cyclic AMP Response Element-Binding Protein/drug effects/*metabolism
MH  - Cysteine Proteinase Inhibitors/pharmacology
MH  - Embryo, Mammalian
MH  - Exons
MH  - Gene Expression Regulation/drug effects
MH  - N-Methylaspartate/pharmacology
MH  - Neurons/cytology/drug effects/*physiology
MH  - Peptide Fragments/*pharmacology
MH  - Phosphorylation
MH  - Potassium Chloride/pharmacology
MH  - Promoter Regions, Genetic
MH  - RNA, Messenger/genetics
MH  - Rats
MH  - Signal Transduction/drug effects/*physiology
MH  - Transcription, Genetic/drug effects/*physiology
EDAT- 2001/03/30 10:00
MHDA- 2001/07/06 10:01
CRDT- 2001/03/30 10:00
PHST- 2001/03/30 10:00 [pubmed]
PHST- 2001/07/06 10:01 [medline]
PHST- 2001/03/30 10:00 [entrez]
AID - S0021-9258(19)31914-3 [pii]
AID - 10.1074/jbc.M010450200 [doi]
PST - ppublish
SO  - J Biol Chem. 2001 May 18;276(20):17301-6. doi: 10.1074/jbc.M010450200. Epub 2001 
      Feb 26.