Parkin deletion causes cerebral and systemic amyloidosis in human mutated tau over-expressing mice.
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(-/-)/Tau(VLW)) mice have altered behaviour and dopamine neurotransmission, tau pathology in brain and amyloid deposition in brain and peripheral organs. PK(-/-)/Tau(VLW) 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 beta-amyloid in the hippocampus. PK(-/-)/Tau(VLW) 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 beta-amyloid deposits caused by over-expression of tau and without modification of the amyloid precursor protein, presenilins or secretases. PK(-/-)/Tau(VLW) mice provide a link between the two proteins more important for the pathogenesis of Alzheimer disease.
Rodríguez-Navarro
Jose A
JA
Department of Neurobiology, Hospital Ramón y Cajal, Madrid, Spain.
Gómez
Ana
A
Rodal
Izaskun
I
Perucho
Juan
J
Martinez
Armando
A
Furió
Vicente
V
Ampuero
Israel
I
Casarejos
María J
MJ
Solano
Rosa M
RM
de Yébenes
Justo García
JG
Mena
Maria A
MA
D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D028226:Amyloidosis, Familial / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001253:Astrocytes / Q000473:pathology; D001522:Behavior, Animal; D001927:Brain Diseases / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D017353:Gene Deletion; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008032:Limbic System / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology; D009154:Mutation; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D011994:Recombinant Proteins / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency* / Q000235:genetics*; D016875:tau Proteins / Q000235:genetics*
D016229:Amyloid beta-Peptides; D018840:HSP70 Heat-Shock Proteins; C054369:MAPT protein, human; D011994:Recombinant Proteins; D016875:tau Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D004298:Dopamine