Implication de l'activité synaptique dans les déficits cognitifs associés au vieillissement et à la maladie d'Alzheimer
|Advisor:||De Koninck, Yves|
|Abstract:||The cognitive decline associated with aging and Alzheimer's disease is a growing concern for public health. The development of therapeutic strategies to maintain cognitive abilities requires proper assessment of the multiple behavioral deficits associated with in animal models of aging as well as of transgenic model of Alzheimer's disease. To identify substrates of these cognitive declines we evaluated the frontal dependent cognitive performance of aged rats and of transgenic mice model of Alzheimer's disease. Our analysis revealed in a subpopulation of aged rats the emergence of abnormal stereotyped exploratory behavior and memory deficits both correlated with a loss of "thin" dendritic spine concomitant with an increase in the synaptic inhibitory tone. In contrast, aged rats resilient to such behavioral impairments exhibit a specific increase in excitatory synaptic inputs at the pyramidal layer 2/3 of the prefrontal cortex. These changes seem underpinned by a change of association of trans-synaptic protein of the Neuroligin family. Beyond memory impairment, Alzheimer's disease is also characterized by many behavioral deficits, such as mood disorders and personality changes, anxiety, aggression, disinhibition. Here we report social behavior alterations similar to those observed in humans. Furthermore our work demonstrates the existence of a behavioral dimorphism reflected at the synaptic level. Indeed we were able to reveal a temporal association between background synaptic hyperactivity and phases of social disinhibition. Finally given the significant synaptic changes observed in Alzheimer's disease, and given the similarity of the social changes observed in certain developmental and neuropsychiatric diseases, we genetically downregulated in a transgenic model of Alzheimer's disease the activity of PAK (p21 activated kinase), a protein involved in actin reorganization and synaptic maturation. Our results suggest for the first time a role of this protein in the process of phosphorylation of tau in the disease. Our findings shed new light on synaptic changes associated with cognitive decline in aging and Alzheimer's disease.|
|Document Type:||Thèse de doctorat|
|Open Access Date:||19 April 2018|
|Collection:||Thèses et mémoires|
All documents in CorpusUL are protected by Copyright Act of Canada.