Publikationsdatum:
2009-02-27
Beschreibung:
A pathological hallmark of Alzheimer's disease is an accumulation of insoluble plaque containing the amyloid-beta peptide of 40-42 amino acid residues. Prefibrillar, soluble oligomers of amyloid-beta have been recognized to be early and key intermediates in Alzheimer's-disease-related synaptic dysfunction. At nanomolar concentrations, soluble amyloid-beta oligomers block hippocampal long-term potentiation, cause dendritic spine retraction from pyramidal cells and impair rodent spatial memory. Soluble amyloid-beta oligomers have been prepared from chemical syntheses, transfected cell culture supernatants, transgenic mouse brain and human Alzheimer's disease brain. Together, these data imply a high-affinity cell-surface receptor for soluble amyloid-beta oligomers on neurons-one that is central to the pathophysiological process in Alzheimer's disease. Here we identify the cellular prion protein (PrP(C)) as an amyloid-beta-oligomer receptor by expression cloning. Amyloid-beta oligomers bind with nanomolar affinity to PrP(C), but the interaction does not require the infectious PrP(Sc) conformation. Synaptic responsiveness in hippocampal slices from young adult PrP null mice is normal, but the amyloid-beta oligomer blockade of long-term potentiation is absent. Anti-PrP antibodies prevent amyloid-beta-oligomer binding to PrP(C) and rescue synaptic plasticity in hippocampal slices from oligomeric amyloid-beta. Thus, PrP(C) is a mediator of amyloid-beta-oligomer-induced synaptic dysfunction, and PrP(C)-specific pharmaceuticals may have therapeutic potential for Alzheimer's disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2748841/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2748841/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lauren, Juha -- Gimbel, David A -- Nygaard, Haakon B -- Gilbert, John W -- Strittmatter, Stephen M -- 5T32GN07205/PHS HHS/ -- P30 DA018343/DA/NIDA NIH HHS/ -- R01 NS039962/NS/NINDS NIH HHS/ -- R01 NS039962-09/NS/NINDS NIH HHS/ -- R01 NS042304/NS/NINDS NIH HHS/ -- R01 NS042304-08/NS/NINDS NIH HHS/ -- R37 NS033020/NS/NINDS NIH HHS/ -- R37 NS033020-17/NS/NINDS NIH HHS/ -- England -- Nature. 2009 Feb 26;457(7233):1128-32. doi: 10.1038/nature07761.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cellular Neuroscience, Neurodegeneration and Repair Program, Yale University School of Medicine, New Haven, Connecticut 06536, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19242475" target="_blank"〉PubMed〈/a〉
Schlagwort(e):
Alzheimer Disease/metabolism/pathology/physiopathology
;
Amyloid Precursor Protein Secretases/metabolism
;
Amyloid beta-Peptides/*chemistry/*metabolism
;
Amyloidosis/metabolism
;
Animals
;
COS Cells
;
Cercopithecus aethiops
;
Hippocampus/cytology/metabolism
;
Humans
;
Long-Term Potentiation/physiology
;
Mice
;
Mice, Inbred C57BL
;
*Neuronal Plasticity
;
Neurons/metabolism
;
Peptide Fragments/*chemistry/*metabolism
;
Prions/genetics/*metabolism
;
Protein Binding
;
*Protein Multimerization
;
Receptors, Cell Surface/genetics/metabolism
;
Synapses/*metabolism/*pathology
Print ISSN:
0028-0836
Digitale ISSN:
1476-4687
Thema:
Biologie
,
Chemie und Pharmazie
,
Medizin
,
Allgemeine Naturwissenschaft
,
Physik
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