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Acta Neuropathologica
Published in: Acta Neuropathologica 1/2012

01-01-2012 | Original Paper

An experimental rat model of sporadic Alzheimer’s disease and rescue of cognitive impairment with a neurotrophic peptide

Authors: Silvia Bolognin, Julie Blanchard, Xiaochuan Wang, Gustavo Basurto-Islas, Yunn Chyn Tung, Erik Kohlbrenner, Inge Grundke-Iqbal, Khalid Iqbal

Published in: Acta Neuropathologica | Issue 1/2012

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Abstract

Alzheimer’s disease (AD) is multifactorial and, to date, no single cause of the sporadic form of this disease, which accounts for over 99% of the cases, has been established. In AD brain, protein phosphatase-2A (PP2A) activity is known to be compromised due to the cleavage and translocation of its potent endogenous inhibitor, I 2 PP2A , from the neuronal nucleus to the cytoplasm. Here, we show that adeno-associated virus vector-induced expression of the N-terminal I2NTF and C-terminal I2CTF halves of I 2 PP2A , also called SET, in brain reproduced key features of AD in Wistar rats. The I2NTF–CTF rats showed a decrease in brain PP2A activity, abnormal hyperphosphorylation and aggregation of tau, a loss of neuronal plasticity and impairment in spatial reference and working memories. To test whether early pharmacologic intervention with a neurotrophic molecule could rescue neurodegeneration and behavioral deficits, 2.5-month-old I2NTF–CTF rats and control littermates were treated for 40 days with Peptide 6, an 11-mer peptide corresponding to an active region of the ciliary neurotrophic factor. Peripheral administration of Peptide 6 rescued neurodegeneration and cognitive deficit in I2NTF–CTF animals by increasing dentate gyrus neurogenesis and mRNA level of brain derived neurotrophic factor. Moreover, Peptide 6-treated I2NTF–CTF rats showed a significant increase in dendritic and synaptic density as reflected by increased expression of synapsin I, synaptophysin and MAP2, especially in the pyramidal neurons of CA1 and CA3 of the hippocampus.
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Metadata
Title
An experimental rat model of sporadic Alzheimer’s disease and rescue of cognitive impairment with a neurotrophic peptide
Authors
Silvia Bolognin
Julie Blanchard
Xiaochuan Wang
Gustavo Basurto-Islas
Yunn Chyn Tung
Erik Kohlbrenner
Inge Grundke-Iqbal
Khalid Iqbal
Publication date
01-01-2012
Publisher
Springer-Verlag
Published in
Acta Neuropathologica / Issue 1/2012
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-011-0908-x

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