Human Molecular Genetics Advance Access originally published online on July 17, 2008
Human Molecular Genetics 2008 17(20):3128-3143; doi:10.1093/hmg/ddn210
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Parkin deletion causes cerebral and systemic amyloidosis in human mutated tau over-expressing mice
1 Department of Neurobiology 2 Department of Neurology, Hospital ‘Ramón y Cajal’, Madrid, Spain 3 Department of Pathology, Hospital Universitario San Carlos, Madrid, Spain 4 Banco de tejidos para Investigaciones Neurológicas and CIBERNED, Madrid, Spain
* To whom correspondence should be addressed at: Departamento de Investigación, Hospital Ramón y Cajal, Ctra. de Colmenar, Km. 9, Madrid 28034, Spain. Tel: +34 913368384; Fax: +34 913369016; Email: maria.a.mena{at}hrc.es
Received May 7, 2008; Accepted July 16, 2008
Deposition of proteins leading to amyloid takes place in some neurodegenerative diseases such as Alzheimer’s disease and Huntington’s disease. Mutations of tau and parkin proteins produce neurofibrillary abnormalities without deposition of amyloid. Here we report that mature, parkin null, over-expressing human mutated tau (PK–/–/TauVLW) mice have altered behaviour and dopamine neurotransmission, tau pathology in brain and amyloid deposition in brain and peripheral organs. PK–/–/TauVLW mice have abnormal behaviour and severe drop out of dopamine neurons in the ventral midbrain, up to 70%, at 12 months and abundant phosphorylated tau positive neuritic plaques, neuro-fibrillary tangles, astrogliosis, microgliosis and plaques of murine β-amyloid in the hippocampus. PK–/–/TauVLW mice have organomegaly of the liver, spleen and kidneys. The electron microscopy of the liver confirmed the presence of a fibrillary protein deposits with amyloid characteristics. There is also accumulation of mouse tau in hepatocytes. These mice have lower levels of CHIP-HSP70, involved in the proteosomal degradation of tau, increased oxidative stress, measured as depletion of glutathione which, added to lack of parkin, could trigger tau accumulation and amyloidogenesis. This model is the first that demonstrates β-amyloid deposits caused by over-expression of tau and without modification of the amyloid precursor protein, presenilins or secretases. PK–/–/TauVLW mice provide a link between the two proteins more important for the pathogenesis of Alzheimer disease.