A novel mouse model for N-terminal truncated Aβ2-x generation through meprin β overexpression in astrocytes
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A novel mouse model for N-terminal truncated Aβ2-x generation through meprin β overexpression in astrocytes. / Armbrust, Fred; Bickenbach, Kira; Altmeppen, Hermann; Foggetti, Angelica; Winkelmann, Anne; Wulff, Peer; Glatzel, Markus; Pietrzik, Claus U; Becker-Pauly, Christoph.
in: CELL MOL LIFE SCI, Jahrgang 81, Nr. 1, 13.03.2024, S. 139.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - A novel mouse model for N-terminal truncated Aβ2-x generation through meprin β overexpression in astrocytes
AU - Armbrust, Fred
AU - Bickenbach, Kira
AU - Altmeppen, Hermann
AU - Foggetti, Angelica
AU - Winkelmann, Anne
AU - Wulff, Peer
AU - Glatzel, Markus
AU - Pietrzik, Claus U
AU - Becker-Pauly, Christoph
N1 - © 2024. The Author(s).
PY - 2024/3/13
Y1 - 2024/3/13
N2 - Neurotoxic amyloid-β (Aβ) peptides cause neurodegeneration in Alzheimer's disease (AD) patients' brains. They are released upon proteolytic processing of the amyloid precursor protein (APP) extracellularly at the β-secretase site and intramembranously at the γ-secretase site. Several AD mouse models were developed to conduct respective research in vivo. Most of these classical models overexpress human APP with mutations driving AD-associated pathogenic APP processing. However, the resulting pattern of Aβ species in the mouse brains differs from those observed in AD patients' brains. Particularly mutations proximal to the β-secretase cleavage site (e.g., the so-called Swedish APP (APPswe) fostering Aβ1-x formation) lead to artificial Aβ production, as N-terminally truncated Aβ peptides are hardly present in these mouse brains. Meprin β is an alternative β-secretase upregulated in brains of AD patients and capable of generating N-terminally truncated Aβ2-x peptides. Therefore, we aimed to generate a mouse model for the production of so far underestimated Aβ2-x peptides by conditionally overexpressing meprin β in astrocytes. We chose astrocytes as meprin β was detected in this cell type in close proximity to Aβ plaques in AD patients' brains. The meprin β-overexpressing mice showed elevated amyloidogenic APP processing detected with a newly generated neo-epitope-specific antibody. Furthermore, we observed elevated Aβ production from endogenous APP as well as AD-related behavior changes (hyperlocomotion and deficits in spatial memory). The novel mouse model as well as the established tools and methods will be helpful to further characterize APP cleavage and the impact of different Aβ species in future studies.
AB - Neurotoxic amyloid-β (Aβ) peptides cause neurodegeneration in Alzheimer's disease (AD) patients' brains. They are released upon proteolytic processing of the amyloid precursor protein (APP) extracellularly at the β-secretase site and intramembranously at the γ-secretase site. Several AD mouse models were developed to conduct respective research in vivo. Most of these classical models overexpress human APP with mutations driving AD-associated pathogenic APP processing. However, the resulting pattern of Aβ species in the mouse brains differs from those observed in AD patients' brains. Particularly mutations proximal to the β-secretase cleavage site (e.g., the so-called Swedish APP (APPswe) fostering Aβ1-x formation) lead to artificial Aβ production, as N-terminally truncated Aβ peptides are hardly present in these mouse brains. Meprin β is an alternative β-secretase upregulated in brains of AD patients and capable of generating N-terminally truncated Aβ2-x peptides. Therefore, we aimed to generate a mouse model for the production of so far underestimated Aβ2-x peptides by conditionally overexpressing meprin β in astrocytes. We chose astrocytes as meprin β was detected in this cell type in close proximity to Aβ plaques in AD patients' brains. The meprin β-overexpressing mice showed elevated amyloidogenic APP processing detected with a newly generated neo-epitope-specific antibody. Furthermore, we observed elevated Aβ production from endogenous APP as well as AD-related behavior changes (hyperlocomotion and deficits in spatial memory). The novel mouse model as well as the established tools and methods will be helpful to further characterize APP cleavage and the impact of different Aβ species in future studies.
KW - Humans
KW - Mice
KW - Animals
KW - Amyloid Precursor Protein Secretases/genetics
KW - Astrocytes/metabolism
KW - Amyloid beta-Protein Precursor/genetics
KW - Amyloid beta-Peptides/metabolism
KW - Alzheimer Disease/metabolism
KW - Proteolysis
KW - Brain/metabolism
U2 - 10.1007/s00018-024-05139-w
DO - 10.1007/s00018-024-05139-w
M3 - SCORING: Journal article
C2 - 38480559
VL - 81
SP - 139
JO - CELL MOL LIFE SCI
JF - CELL MOL LIFE SCI
SN - 1420-682X
IS - 1
ER -