TY  - JOUR
KW  - Alzheimer?s disease
KW  -  Beta amyloid
KW  -  Down Syndrome
KW  -  Mass spectrometry
ID  - discovery10126443
UR  - https://doi.org/10.1016/j.neulet.2021.135894
VL  - 754
A1  - Gkanatsiou, E
A1  - Sahlin, C
A1  - Portelius, E
A1  - Johannesson, M
A1  - Söderberg, L
A1  - Fälting, J
A1  - Basun, H
A1  - Möller, C
A1  - Odergren, T
A1  - Zetterberg, H
A1  - Blennow, K
A1  - Lannfelt, L
A1  - Brinkmalm, G
N2  - The major characteristics of Alzheimer's disease (AD) are amyloid plaques, consisting of aggregated beta amyloid (A?) peptides, together with tau pathology (tangles, neuropil treads and dystrophic neurites surrounding the plaques), in the brain. Down's syndrome (DS) individuals are at increased risk to develop AD-type pathology; most DS individuals have developed substantial pathology already at the age of 40. DS individuals have an extra copy of chromosome 21, harbouring the amyloid precursor protein gene (APP). Our aim was to investigate the A? peptide pattern in DS and AD brains to investigate differences in their amyloid deposition and aggregation, respectively. Cortical tissue from patients with DS (with amyloid pathology), sporadic AD and controls were homogenized and fractionated into TBS (water soluble) and formic acid (water insoluble) fractions. Immunoprecipitation (IP) was performed using a variety of antibodies targeting different A? species including oligomeric A?. Mass spectrometry was then used to evaluate the presence of A? species in the different patient groups. A large number of A? peptides were identified including A?1-X, 2-X, 3-X, 4-X, 5-X, 11-X, and A? peptides extended N terminally of the BACE1 cleavage site and ending at amino 15 in the A? sequence APP/A?(-X to 15), as well as peptides post-translationally modified by pyroglutamate formation. Most A? peptides had higher abundance in AD and DS compared to controls, except the APP/A?(-X to 15) peptides which were most abundant in DS followed by controls and AD. Furthermore, the abundancies of A?X-40 and A?X-34 were increased in DS compared with AD. A?1-40, A?1-42, and A?4-42 were identified as the main constitutes of protofibrils (IP'd using mAb158) and higher relative A?1-42 signals were obtained compared with samples IP'd with 6E10?+?4G8, indicating that the protofibrils/oligomers were enriched with peptides ending at amino acid 42. All A? peptides found in AD were also present in DS indicating similar pathways of A? peptide production, degradation and accumulation, except for APP/A?(-X to 15). Likewise, the A? peptides forming protofibrils/oligomers in both AD and DS were similar, implying the possibility that treatment with clinical benefit in sporadic AD might also be beneficial for subjects with DS.
AV  - public
JF  - Neuroscience Letters
TI  - Characterization of monomeric and soluble aggregated A? in Down's syndrome and Alzheimer's disease brains
Y1  - 2021/04/10/
N1  - This work is licensed under a Creative Commons Attribution 4.0 International License. The images
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ER  -