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Acta Neuropathologica Communications
Published in: Acta Neuropathologica Communications 1/2014

Open Access 01-12-2014 | Research

Intracellular Aβ pathology and early cognitive impairments in a transgenic rat overexpressing human amyloid precursor protein: a multidimensional study

Authors: M Florencia Iulita, Simon Allard, Luise Richter, Lisa-Marie Munter, Adriana Ducatenzeiler, Christoph Weise, Sonia Do Carmo, William L Klein, Gerhard Multhaup, A Claudio Cuello

Published in: Acta Neuropathologica Communications | Issue 1/2014

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Abstract

Numerous studies have implicated the abnormal accumulation of intraneuronal amyloid-β (Aβ) as an important contributor to Alzheimer’s disease (AD) pathology, capable of triggering neuroinflammation, tau hyperphosphorylation and cognitive deficits. However, the occurrence and pathological relevance of intracellular Aβ remain a matter of controversial debate. In this study, we have used a multidimensional approach including high-magnification and super-resolution microscopy, cerebro-spinal fluid (CSF) mass spectrometry analysis and ELISA to investigate the Aβ pathology and its associated cognitive impairments, in a novel transgenic rat model overexpressing human APP. Our microscopy studies with quantitative co-localization analysis revealed the presence of intraneuronal Aβ in transgenic rats, with an immunological signal that was clearly distinguished from that of the amyloid precursor protein (APP) and its C-terminal fragments (CTFs). The early intraneuronal pathology was accompanied by a significant elevation of soluble Aβ42 peptides that paralleled the presence and progression of early cognitive deficits, several months prior to amyloid plaque deposition. Aβ38, Aβ39, Aβ40 and Aβ42 peptides were detected in the rat CSF by MALDI-MS analysis even at the plaque-free stages; suggesting that a combination of intracellular and soluble extracellular Aβ may be responsible for impairing cognition at early time points. Taken together, our results demonstrate that the intraneuronal development of AD-like amyloid pathology includes a mixture of molecular species (Aβ, APP and CTFs) of which a considerable component is Aβ; and that the early presence of these species within neurons has deleterious effects in the CNS, even before the development of full-blown AD-like pathology.
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Metadata
Title
Intracellular Aβ pathology and early cognitive impairments in a transgenic rat overexpressing human amyloid precursor protein: a multidimensional study
Authors
M Florencia Iulita
Simon Allard
Luise Richter
Lisa-Marie Munter
Adriana Ducatenzeiler
Christoph Weise
Sonia Do Carmo
William L Klein
Gerhard Multhaup
A Claudio Cuello
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Acta Neuropathologica Communications / Issue 1/2014
Electronic ISSN: 2051-5960
DOI
https://doi.org/10.1186/2051-5960-2-61

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