title: Beta-amyloid overload does not directly correlate with SAPK/JNK activation and tau protein phosphorylation in the cerebellar cortex of Ts65Dn mice.
abstract: It is known that in the nervous tissue beta-amyloid overproduction and its extracellular or intracellular deposition can activate mitogen-activated protein kinases involved in tau protein phosphorylation. Hyperphosphorylated tau is not more able to bind neuron microtubules, leading to their disassembly and axon degeneration. We have previously described that at 10 months of age in the cerebellum of Ts65Dn mice, which are partially trisomic for the chromosome 16 and are considered a valuable model for Down syndrome, Purkinje cells undergo axon degeneration. Taking into consideration that Ts65Dn mice carry three copies of the gene encoding for the amyloid precursor protein, to characterize potential signaling events triggering the degenerative phenomenon, specific antibodies were used to examine the role of beta-amyloid overload in the activation of the stress activated kinase/c-jun N-terminal kinase (SAPK/JNK) and tau protein phosphorylation in the cerebellar cortex of 12-month-old Ts65Dn mice. We found small extracellular deposits of beta-amyloid at the borderline between the granule cell layer and the white matter, i.e., in the vicinity of the area where calbindin immunostaining of Purkinje cell axons revealed clusters of newly formed terminals of injured axons. Moreover, intracellular deposits were present in the somata of Purkinje cells. The level of activation of SAPK/JNK was greatly increased. The activation occurred in the "pinceaux" made by basket interneuron axons at the axon hillock of Purkinje cells. Antibody directed against tau protein phosphorylated at Ser-396/Ser-404 revealed positive NG2 cells and Bergman fibers in the molecular layer and oligodendrocytes in the white matter. Data indicate that beta-amyloid extracellular deposits could have exerted a local cytotoxic effect, leading to Purkinje cell axon degeneration. The activation of SAPK/JNK in basket cell "pinceaux" may be a consequence of altered functionality of Purkinje cells and may represent an attempt of basket cells of synaptic remodeling. Moreover, the findings for tau protein phosphorylation suggest that Ts65Dn mice are affected by a cerebellar glial tauopathy.
authors.affiliation: Dipartimento di Biologia Animale, Laboratorio di Biologia Cellulare e Neurobiologia, Università di Pavia, piazza Botta 10, 27100 Pavia, Italy.
authors.forename: Selene
authors.initials: S
authors.lastname: Lomoio
authors.forename: Elda
authors.initials: E
authors.lastname: Scherini
authors.forename: Daniela
authors.initials: D
authors.lastname: Necchi
mesh_terms: D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D002531:Cerebellum / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D007395:Interneurons / Q000378:metabolism / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D024801:Tauopathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014314:Trisomy / Q000235:genetics*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016875:tau Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8