Globular amyloid beta-peptide oligomer - a homogenous and stable neuropathological protein in Alzheimer's disease.
Amyloid beta-peptide (Abeta)(1-42) oligomers have recently been discussed as intermediate toxic species in Alzheimer's disease (AD) pathology. Here we describe a new and highly stable Abeta(1-42) oligomer species which can easily be prepared in vitro and is present in the brains of patients with AD and Abeta(1-42)-overproducing transgenic mice. Physicochemical characterization reveals a pure, highly water-soluble globular 60-kDa oligomer which we named 'Abeta(1-42) globulomer'. Our data indicate that Abeta(1-42) globulomer is a persistent structural entity formed independently of the fibrillar aggregation pathway. It is a potent antigen in mice and rabbits eliciting generation of Abeta(1-42) globulomer-specific antibodies that do not cross-react with amyloid precursor protein, Abeta(1-40) and Abeta(1-42) monomers and Abeta fibrils. Abeta(1-42) globulomer binds specifically to dendritic processes of neurons but not glia in hippocampal cell cultures and completely blocks long-term potentiation in rat hippocampal slices. Our data suggest that Abeta(1-42) globulomer represents a basic pathogenic structural principle also present to a minor extent in previously described oligomer preparations and that its formation is an early pathological event in AD. Selective neutralization of the Abeta globulomer structure epitope is expected to have a high potential for treatment of AD.
Barghorn
Stefan
S
Neuroscience Discovery Research, Abbott GmbH and Co. KG, Ludwigshafen, Germany.
Nimmrich
Volker
V
Striebinger
Andreas
A
Krantz
Carsten
C
Keller
Patrick
P
Janson
Bodo
B
Bahr
Michael
M
Schmidt
Martin
M
Bitner
Robert S
RS
Harlan
John
J
Barlow
Eve
E
Ebert
Ulrich
U
Hillen
Heinz
H
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D000906:Antibodies; D000918:Antibody Specificity; D002478:Cells, Cultured; D000939:Epitopes / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D005227:Fatty Acids; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D017774:Long-Term Potentiation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011487:Protein Conformation; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D014867:Water / Q000378:metabolism
D016229:Amyloid beta-Peptides; D000906:Antibodies; D000939:Epitopes; D005227:Fatty Acids; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D014867:Water