Novel Phosphorylation-State Specific Antibodies Reveal Differential Deposition of Ser26 Phosphorylated Aβ Species in a Mouse Model of Alzheimer's Disease.
Novel Phosphorylation-State Specific Antibodies Reveal Differential Deposition of Ser26 Phosphorylated Aβ Species in a Mouse Model of Alzheimer's Disease.pdf
[en] Aggregation and deposition of amyloid-β (Aβ) peptides in extracellular plaques and in the cerebral vasculature are prominent neuropathological features of Alzheimer's disease (AD) and closely associated with the pathogenesis of AD. Amyloid plaques in the brains of most AD patients and transgenic mouse models exhibit heterogeneity in the composition of Aβ deposits, due to the occurrence of elongated, truncated, and post-translationally modified Aβ peptides. Importantly, changes in the deposition of these different Aβ variants are associated with the clinical disease progression and considered to mark sequential phases of plaque and cerebral amyloid angiopathy (CAA) maturation at distinct stages of AD. We recently showed that Aβ phosphorylated at serine residue 26 (pSer26Aβ) has peculiar characteristics in aggregation, deposition, and neurotoxicity. In the current study, we developed and thoroughly validated novel monoclonal and polyclonal antibodies that recognize Aβ depending on the phosphorylation-state of Ser26. Our results demonstrate that selected phosphorylation state-specific antibodies were able to recognize Ser26 phosphorylated and non-phosphorylated Aβ with high specificity in enzyme-linked immunosorbent assay (ELISA) and Western Blotting (WB) assays. Furthermore, immunofluorescence analyses with these antibodies demonstrated the occurrence of pSer26Aβ in transgenic mouse brains that show differential deposition as compared to non-phosphorylated Aβ (npAβ) or other modified Aβ species. Notably, pSer26Aβ species were faintly detected in extracellular Aβ plaques but most prominently found intraneuronally and in cerebral blood vessels. In conclusion, we developed new antibodies to specifically differentiate Aβ peptides depending on the phosphorylation state of Ser26, which are applicable in ELISA, WB, and immunofluorescence staining of mouse brain tissues. These site- and phosphorylation state-specific Aβ antibodies represent novel tools to examine phosphorylated Aβ species to further understand and dissect the complexity in the age-related and spatio-temporal deposition of different Aβ variants in transgenic mouse models and human AD brains.
Disciplines :
Neurology
Author, co-author :
Kumar, Sathish; Department of Neurology, University of Bonn Medical Center, Bonn, Germany
Kapadia, Akshay; Department of Neurology, University of Bonn Medical Center, Bonn, Germany
Theil, Sandra; Department of Neurology, University of Bonn Medical Center, Bonn, Germany
Joshi, Pranav; Department of Neurology, University of Bonn Medical Center, Bonn, Germany
Riffel, Florian; Department of Neurology, University of Bonn Medical Center, Bonn, Germany
HENEKA, Michael ; Department of Neurodegenerative Diseases and Geropsychiatry, Neurology, University of Bonn Medical Center, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Walter, Jochen; Department of Neurology, University of Bonn Medical Center, Bonn, Germany
External co-authors :
yes
Language :
English
Title :
Novel Phosphorylation-State Specific Antibodies Reveal Differential Deposition of Ser26 Phosphorylated Aβ Species in a Mouse Model of Alzheimer's Disease.
We thank the Microscopy Core Facility of the Medical Faculty at the University of Bonn for providing their help and services. Funding. We acknowledge Deutsche Forschungsgemeinschaft [grant #WA1477/6-3 (JW)] and the Alzheimer Forschungs Initiative e.V. [grants #12854 and #17011 (SK)] for research funding.We acknowledge Deutsche Forschungsgemeinschaft [grant #WA1477/6-3 (JW)] and the Alzheimer Forschungs Initiative e.V. [grants #12854 and #17011 (SK)] for research funding.
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