title: Cerebrolysin™ efficacy in a transgenic model of tauopathy: role in regulation of mitochondrial structure.
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 Cerebrolysin™ (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.
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.forename: Kiren
authors.initials: K
authors.lastname: Ubhi
authors.forename: Margarita
authors.initials: M
authors.lastname: Trejo
authors.forename: Michael
authors.initials: M
authors.lastname: Mante
authors.forename: Christina
authors.initials: C
authors.lastname: Patrick
authors.forename: Anthony
authors.initials: A
authors.lastname: Adame
authors.forename: Philipp
authors.initials: P
authors.lastname: Novak
authors.forename: Marion
authors.initials: M
authors.lastname: Jech
authors.forename: Edith
authors.initials: E
authors.lastname: Doppler
authors.forename: Herbert
authors.initials: H
authors.lastname: Moessler
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA. emasliah@ucsd.edu.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
mesh_terms: D000375:Aging; D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D034281:Dynamins / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017966:Pyramidal Cells / Q000187:drug effects / Q000473:pathology; D024801:Tauopathies / Q000188:drug therapy* / Q000473:pathology*; D013702:Temporal Lobe / Q000187:drug effects / Q000473:pathology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000596:Amino Acids; C054369:MAPT protein, human; D018696:Neuroprotective Agents; D016875:tau Proteins; C006952:cerebrolysin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; C486391:Dnm1l protein, mouse; D034281:Dynamins