Motor coordination and synaptic plasticity deficits are associated with increased cerebellar activity of NADPH oxidase, CAMKII, and PKC at preplaque stage in the TgCRND8 mouse model of Alzheimer's disease

• DOI: 10.1016/j.neurobiolaging.2018.02.025
• Publication Date: 2018-03-05T12:13:59Z
• Authors: Roberto Russo; Fabio Cattaneo; Pellegrino Lippiello; Claudia Cristiano; Fabio Zurlo; Martina Castaldo; Carlo Irace; Tiziana Borsello; Rita Santamaria; Rosario Ammendola; Antonio Calignano; Maria Concetta Mi...
• Keywords: Male; 0301 basic medicine; Patch-Clamp Techniques; Protein Kinase C-alpha; Gene Expression; Mice, Transgenic; In Vitro Techniques; Synaptic plasticity; Amyloid beta-Protein Precursor; Norepinephrine; 03 medical and health sciences; Alzheimer Disease; Patch-clamp recordings; Cerebellum; Animals; Alzheimer's disease; beta-amyloid; Synaptic plasticity; Noradrenaline; Oxidative stress; Patch-clamp recordings; Genetic Association Studies; Neuronal Plasticity; beta-amyloid; NADPH Oxidases; Alzheimer's disease; 3. Good health; Alzheimer's disease; Noradrenaline; oxidative stress; patch-clamp recordings; synaptic plasticity; β-amyloid; neuroscience (all); aging; neurology (clinical); developmental biology; geriatrics and gerontology; Disease Models, Animal; Oxidative Stress; Oxidative stress; Noradrenaline; Female; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Psychomotor Performance

Numerous studies indicate that the cerebellum undergoes structural and functional neurodegenerative changes in Alzheimer's disease. The purpose of this study was to examine the extent of cerebellar alterations at early, preplaque stage of the pathology in TgCRND8 mice through behavioral, electrophysiological, and molecular analysis. Balance beam test and foot-printing analysis revealed significant motor coordination and balance deficits in 2-month-old TgCRND8 mice compared to their littermates. Patch-clamp recordings performed on cerebellar slices of transgenic mice showed synaptic plasticity deficit and loss of noradrenergic modulation at parallel fiber-Purkinje cell synapse suggesting an early dysfunction of the cerebellar circuitry due to amyloid precursor protein overexpression. Finally, western blot analysis revealed an enhanced expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits p47phox and p67phox as well as Ca2+/calmodulin-dependent protein kinase and protein kinase C alpha in the cerebellum of 2-month-old transgenic mice. Therefore, we propose the existence of self-sustaining feedback loop involving the formyl peptide receptor 2-reactive oxygen species-Ca2+/calmodulin-dependent protein kinase II-protein kinase C alpha pathway that may promote reactive oxygen species generation in the early stage of Alzheimer's disease and eventually contribute to the exacerbation of pathological phenotype.