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Acta Neuropathol Commun. 2017 Jun 20;5(1):49. doi: 10.1186/s40478-017-0448-2.

Expression of endogenous mouse APP modulates β-amyloid deposition in hAPP-transgenic mice.

Author information

1
University of Lübeck (UzL), LIED, Lübeck, Germany.
2
Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo (UiO) / Oslo Universiy Hospital (OUS), Postboks 4950 Nydalen, Oslo, 0424, Norway.
3
Institute for Pathobiochemistry, University Medical Center of the Johannes-Gutenberg-University, Mainz, Germany.
4
Department of Physical Organic Chemistry, Latvian Institute of Organic Synthesis (OSI), Riga, Latvia.
5
Faculty of Medicine, Department of Pharmacology, University of Latvia (LU), Riga, Latvia.
6
Center for Health & Bioresources, Austrian Institute of Technology GmbH (AIT), Seibersdorf, Austria.
7
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
8
Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo (UiO) / Oslo Universiy Hospital (OUS), Postboks 4950 Nydalen, Oslo, 0424, Norway. jens.pahnke@medisin.uio.no.
9
University of Lübeck (UzL), LIED, Lübeck, Germany. jens.pahnke@medisin.uio.no.
10
Leibniz Institute for of Plant Biochemistry (IPB), Halle, Germany. jens.pahnke@medisin.uio.no.

Abstract

Amyloid-β (Aβ) deposition is one of the hallmarks of the amyloid hypothesis in Alzheimer's disease (AD). Mouse models using APP-transgene overexpression to generate amyloid plaques have shown to model only certain parts of the disease. The extent to which the data from mice can be transferred to man remains controversial. Several studies have shown convincing treatment results in reducing Aβ and enhancing cognition in mice but failed totally in human. One model-dependent factor has so far been almost completely neglected: the endogenous expression of mouse APP and its effects on the transgenic models and the readout for therapeutic approaches.Here, we report that hAPP-transgenic models of amyloidosis devoid of endogenous mouse APP expression (mAPP-knockout / mAPPko) show increased amounts and higher speed of Aβ deposition than controls with mAPP. The number of senile plaques and the level of aggregated hAβ were elevated in mAPPko mice, while the deposition in cortical blood vessels was delayed, indicating an alteration in the general aggregation propensity of hAβ together with endogenous mAβ. Furthermore, the cellular response to Aβ deposition was modulated: mAPPko mice developed a pronounced and age-dependent astrogliosis, while microglial association to amyloid plaques was diminished. The expression of human and murine aggregation-prone proteins with differing amino acid sequences within the same mouse model might not only alter the extent of deposition but also modulate the route of pathogenesis, and thus, decisively influence the study outcome, especially in translational research.

KEYWORDS:

Abeta; Alzheimer’s disease; Amyloid precursor protein; Amyloidosis; Murine amyloid-beta; Transgenic mice

PMID:
28637503
PMCID:
PMC5480119
DOI:
10.1186/s40478-017-0448-2
[Indexed for MEDLINE]
Free PMC Article

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