title: The effects of parkin suppression on the behaviour, amyloid processing, and cell survival in APP mutant transgenic mice.
abstract: Parkin suppression induces accumulation of beta-amyloid in mutant tau mice. We studied the effect of parkin suppression on behaviour and brain pathology in APP(swe) mutant mice. We produced double mutant mice with human mutated APP(swe)+partial (hemizygote) or total (homozygote) deletion of Park-2 gene. We studied the development, behaviour, brain histology, and biochemistry of 12- and 16-month-old animals in 6 groups of mice, with identical genetic background: wild-type (WT), APP(swe) overexpressing (APP), hemizygote and homozygote deletion of Park-2 (PK(+/-) and PK(-/-), respectively), and double mutants (APP/PK(+/-) and APP/PK(-/-)). APP mice have reduced weight gain, decreased motor activity, and reduced number of entrances and of arm alternation in the Y-maze, abnormalities which were partially or completely normalized in APP/PK(+/-) and APP/PK(-/-) mice. The double mutants had similar number of mutant human APP transgene copies than the APP and levels of 40 and 80 kDa proteins; but both of them, APP/PK(+/-) and APP/PK(-/-) mice, had less plaques in cortex and hippocampus than the APP mice. APP mutant mice had increased apoptosis, proapoptotic Bax/Bcl2 ratios, and gliosis, but these death-promoting factors were normalized in APP/PK(+/-) and APP/PK(-/-) mice. APP mutant mice had an increased number of tau immunoreactive neuritic plaques in the cerebral cortex as well as increased levels of total and phosphorylated tau protein, and these changes were partially normalized in APP/PK(+/-) heterozygotic and homozygotic APP/PK(-/-) mice. Compensatory protein-degrading systems such as HSP70, CHIP, and macroautophagy were increased in APP/PK(+/-) and APP/PK(-/-). Furthermore, the chymotrypsin- and trypsin-like proteasome activities, decreased in APP mice in comparison with WT, were normalized in the APP/PK(-/-) mice. We proposed that partial and total suppression of parkin triggers compensatory mechanisms, such as chaperone overexpression and increased autophagy, which improved the behavioural and cellular phenotype of APP(swe) mice.
authors.affiliation: Department of Neurobiology, Hospital Ramón y Cajal, Madrid, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Perucho
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Casarejos
authors.forename: Isabel
authors.initials: I
authors.lastname: Rubio
authors.forename: José A
authors.initials: JA
authors.lastname: Rodriguez-Navarro
authors.forename: Ana
authors.initials: A
authors.lastname: Gómez
authors.forename: Israel
authors.initials: I
authors.lastname: Ampuero
authors.forename: Izaskun
authors.initials: I
authors.lastname: Rodal
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Solano
authors.forename: Eva
authors.initials: E
authors.lastname: Carro
authors.forename: Justo
authors.initials: J
authors.lastname: García de Yébenes
authors.forename: Maria A
authors.initials: MA
authors.lastname: Mena
mesh_terms: D000367:Age Factors; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003072:Cognition Disorders / Q000235:genetics; D005106:Exploratory Behavior / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000235:genetics; D020287:In Situ Nick-End Labeling / Q000379:methods; D007398:Interpersonal Relations; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000378:metabolism; D009043:Motor Activity / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D010446:Peptide Fragments / Q000378:metabolism; D045442:Rotarod Performance Test / Q000379:methods; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D005904:Glial Fibrillary Acidic Protein; D018832:Molecular Chaperones; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein