Identification of low molecular weight pyroglutamate A{beta} oligomers in Alzheimer disease: a novel tool for therapy and diagnosis.
N-terminally truncated Aβ peptides starting with pyroglutamate (AβpE3) represent a major fraction of all Aβ peptides in the brain of Alzheimer disease (AD) patients. AβpE3 has a higher aggregation propensity and stability and shows increased toxicity compared with full-length Aβ. In the present work, we generated a novel monoclonal antibody (9D5) that selectively recognizes oligomeric assemblies of AβpE3 and studied the potential involvement of oligomeric AβpE3 in vivo using transgenic mouse models as well as human brains from sporadic and familial AD cases. 9D5 showed an unusual staining pattern with almost nondetectable plaques in sporadic AD patients and non-demented controls. Interestingly, in sporadic and familial AD cases prominent intraneuronal and blood vessel staining was observed. Using a novel sandwich ELISA significantly decreased levels of oligomers in plasma samples from patients with AD compared with healthy controls were identified. Moreover, passive immunization of 5XFAD mice with 9D5 significantly reduced overall Aβ plaque load and AβpE3 levels, and normalized behavioral deficits. These data indicate that 9D5 is a therapeutically and diagnostically effective monoclonal antibody targeting low molecular weight AβpE3 oligomers.
Wirths
Oliver
O
Department of Molecular Psychiatry and Alzheimer, Graduate School, University Medicine Goettingen, 37075 Goettingen, Germany.
Erck
Christian
C
Martens
Henrik
H
Harmeier
Anja
A
Geumann
Constanze
C
Jawhar
Sadim
S
Kumar
Sathish
S
Multhaup
Gerd
G
Walter
Jochen
J
Ingelsson
Martin
M
Degerman-Gunnarsson
Malin
M
Kalimo
Hannu
H
Huitinga
Inge
I
Lannfelt
Lars
L
Bayer
Thomas A
TA
D000544:Alzheimer Disease / Q000378:metabolism*; D000682:Amyloid / Q000737:chemistry; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D002845:Chromatography / Q000379:methods; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006801:Humans; D007120:Immunochemistry / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008970:Molecular Weight; D017434:Protein Structure, Tertiary; D011761:Pyrrolidonecarboxylic Acid / Q000737:chemistry*; D019076:Transgenes
D000682:Amyloid; D011761:Pyrrolidonecarboxylic Acid