A novel mouse model for N-terminal truncated Aβ2-x generation through meprin β overexpression in astrocytes

TY - JOUR

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 -