Cycle 2 project 8

Project 8: Cellular, molecular and systems-level mechanisms underlying the establishment of a brain cognitive reserve in a mouse model of Alzheimer’s disease


PhD student: Senka Hadžibegović, Serbia,
Home Institute: Bordeaux Neurocampus; Principle Investigator: Bruno Bontempi,
Host Institute: Neuroscience Center Zürich; Principle Investigator: Isabelle Mansuy

Executive Summary
The “cognitive reserve” model suggests that individuals with greater brain reserve capacity (i.e. with higher level of education or occupational attainment) may develop resilience to neurodegenerative damage and optimize behavioral abilities through differential recruitment of neural networks and/or alternative cognitive strategies. Our preliminary data highlight the beneficial effects of exposure to environmental enrichment (EE) used as a rehabilitative therapy in rodents. Building upon these solid results, the goal of this 4 year project is to unravel some of the mechanisms by which EE: (1) reduces/delays the onset of memory deficits associated with Alzheimer’s disease (AD) and (2) delays the occurrence of neuropathological brain markers such as amyloid deposits during the aging process.

We hypothesize that the beneficial effects of enrichment could rely on long-lasting and stable modifications of the cerebral networks involved in cognitive functions. The originality of our approach lies in administering EE early in life and for a timerestricted period to enable long-lasting cerebral modifications in the form of a “cognitive reserve”. To mimic AD pathology, a well characterized transgenic mouse model of this disease will be used (i.e. Tg2576 transgenic mice exhibiting a slow time-related progression of the disease suitable to accommodate specific exposures to EE) to characterize the cellular and molecular mechanisms underlying the establishment of this cognitive reserve that could later in life make brain functions more resilient to the deleterious effects of AD. The proposed experiments, organized in the form of 5 interdependent tasks, will benefit from the collaborative efforts of 2 teams (one in Bordeaux, the other in Zurich) with a high level of complementary expertise in the fields of Cognitive and Molecular Neuroscience as well as Vascular Physiology. Task 1 will characterize the kinetic of effects of EE on memory function in AD (Tg2576) mice (Bordeaux team). Task 2 will map the dynamics of reorganization of hippocampal-cortical networks during spatial memory processing in AD mice exposed to EE (Bordeaux team). Characterization of the EE-induced reorganization and reactivity of the vascular network in AD mice will be accomplished in Task 3 (Bordeaux team). Finally, Tasks 4 and 5 will explore amyloidogenesis in both neuronal and vascular compartments in AD mice and the modulation by EE of hippocampal neurogenesis and epigenetics in extrahippocampal brains regions in AD mice (Bordeaux and Zurich teams).

The strength of our proposal resides in the fact that it is based on an integrative approach combining state-of-the art animal model of AD, cellular imaging of activitydependent genes, biomarkers of AD’s progression and confocal microscopy of the activity of blood vessels (team 1 based in Bordeaux, principle investigators Bruno Bontempi), molecular biology and learning and   memory function with an emphasis on epigenetic mechanisms (team 2, co-principle investigator Isabelle Mansuy). We anticipate that the work described in this project may open new avenues for clinical research in the field of human neurological disorders where application of EE paradigms, alone or in combination with pharmacological treatments, might emerge as a pertinent therapeutic strategy in the near future.

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