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PMID: 20037574 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Amyloid beta from axons and dendrites reduces local spine number and plasticity.

Nature neuroscience ·Vol. 13 ·No. 2 ·2010-02-00 ·Pages 190-6

Wei W, Nguyen LN, Kessels HW, Hagiwara H, Sisodia S, Malinow R

Abstract

Excessive synaptic loss is thought to be one of the earliest events in Alzheimer's disease. Amyloid beta (Abeta), a peptide secreted in an activity-modulated manner by neurons, has been implicated in the pathogenesis of Alzheimer's disease by removing dendritic spines, sites of excitatory synaptic transmission. However, issues regarding the subcellular source of Abeta, as well as the mechanisms of its production and actions that lead to synaptic loss, remain poorly understood. In rat organotypic slices, we found that acute overproduction of either axonal or dendritic Abeta reduced spine density and plasticity at nearby ( approximately 5-10 mum) dendrites. The production of Abeta and its effects on spines were sensitive to blockade of action potentials or nicotinic receptors; the effects of Abeta (but not its production) were sensitive to NMDA receptor blockade. Notably, only 30-60 min blockade of Abeta overproduction permitted induction of plasticity. Our results indicate that continuous overproduction of Abeta at dendrites or axons acts locally to reduce the number and plasticity of synapses.

MeSH Terms
Action Potentials/physiology Amyloid beta-Peptides/metabolism Amyloid beta-Protein Precursor/metabolism Animals Axons/metabolism,physiology Dendrites/metabolism,physiology Dendritic Spines/physiology Hippocampus/metabolism,physiology In Vitro Techniques Neuronal Plasticity/physiology Peptide Fragments/metabolism Pyramidal Cells/metabolism,physiology Rats Receptors, N-Methyl-D-Aspartate/metabolism Receptors, Nicotinic/metabolism Synapses/physiology Time Factors
Chemicals
Amyloid beta-Peptides Amyloid beta-Protein Precursor Peptide Fragments Receptors, N-Methyl-D-Aspartate Receptors, Nicotinic amyloid beta-protein (1-42)
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Wei Wei
Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
Nguyen Louis N
Kessels Helmut W
Hagiwara Hiroaki
Sisodia Sangram
Malinow Roberto
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Article Info
Journal
Nature neuroscience
Abbr.
Nat Neurosci
ISSN
1546-1726
DOI
10.1038/nn.2476
Published
2010-02-00
Epub
2009-00-27
Pages
190-6
Language
English
Region
United States
NLM ID
9809671
PMCID
PMC3310198
Subset
IM
Grants
NIMH NIH HHS · R01 MH049159-09 · United States
NIA NIH HHS · R01 AG032132-17 · United States
NIMH NIH HHS · R01 MH049159-22 · United States
NIGMS NIH HHS · T32 GM008444 · United States
NIMH NIH HHS · R01 MH049159-21 · United States
NIA NIH HHS · R01 AG032132 · United States
NIA NIH HHS · R01 AG032132-14 · United States
NIA NIH HHS · R01 AG032132-15 · United States
NINDS NIH HHS · R01 NS032827 · United States
NIMH NIH HHS · R01 MH049159 · United States
External Links
PubMed source DOI: 10.1038/nn.2476 PMC Full Text View journal details
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