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Open Access Highly Accessed Research article

Cerebrolysin™ efficacy in a transgenic model of tauopathy: role in regulation of mitochondrial structure

Edward Rockenstein1, Kiren Ubhi1, Margarita Trejo1, Michael Mante1, Christina Patrick1, Anthony Adame1, Philipp Novak2, Marion Jech2, Edith Doppler2, Herbert Moessler2 and Eliezer Masliah13*

Author Affiliations

1 Department of Neurosciences, University of California San Diego, La Jolla, CA, USA

2 Clinical Research & Pharmacology, EVER Neuro Pharma GmbH, Unterach, Austria

3 Department of Pathology, University of California San Diego, La Jolla, CA, USA

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BMC Neuroscience 2014, 15:90  doi:10.1186/1471-2202-15-90

Published: 21 July 2014

Abstract

Background

Alzheimer’s Disease (AD) and Fronto temporal lobar dementia (FTLD) are common causes of dementia in the aging population for which limited therapeutical options are available. These disorders are associated with Tau accumulation. We have previously shown that CerebrolysinTM (CBL), a neuropeptide mixture with neurotrophic effects, ameliorates the behavioral deficits and neuropathological alterations in amyloid precursor protein (APP) transgenic (tg) mouse model of AD by reducing hyper-phosphorylated Tau. CBL has been tested in clinical trials for AD, however it’s potential beneficial effects in FTLD are unknown. For this purpose we sought to investigate the effects of CBL in a tg model of tauopathy. Accordingly, double tg mice expressing mutant Tau under the mThy-1 promoter and GSK3β (to enhance Tau phosphorylation) were treated with CBL and evaluated neuropathologically.

Results

Compared to single Tau tg mice the Tau/GSK3β double tg model displayed elevated levels of Tau phosphorylation and neurodegeneration in the hippocampus. CBL treatment reduced the levels of Tau phosphorylation in the dentate gyrus and the degeneration of pyramidal neurons in the temporal cortex and hippocampus of the Tau/GSK3β double tg mice. Interestingly, the Tau/GSK3β double tg mice also displayed elevated levels of Dynamin-related protein-1 (Drp-1), a protein that hydrolyzes GTP and is required for mitochondrial division. Ultrastructural analysis of the mitochondria in the Tau/GSK3β double tg mice demonstrated increased numbers and fragmentation of mitochondria in comparison to non-tg mice. CBL treatment normalized levels of Drp-1 and restored mitochondrial structure.

Conclusions

These results suggest that the ability of CBL to ameliorate neurodegenerative pathology in the tauopathy model may involve reducing accumulation of hyper-phosphorylated Tau and reducing alterations in mitochondrial biogenesis associated with Tau.

Keywords:
Tau; GSK3β; Drp-1; Neuroprotection; Alzheimer’s disease; Tauopathies