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Projekt
Analysis of the detrimental effects of Cnr1-/- mice in an Alzheimer's mouse model and of the interplay between CB1 receptor function and amyloid precursor protein processing
Antragsteller
Professor Dr. Christian Behl
Fachliche Zuordnung
Biologische Psychiatrie
Förderung
Förderung von 2008 bis 2014
Projektkennung
Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 42860621
To study the interplay between the endocannabinoid system and Alzheimer’s disease (AD), we established a novel transgenic mouse model, a k.o. of CB1 in a well-known AD mouse (APP23) in the first funding period. APP23/Cnr1-/- mice showed lower birth rate and body weight and a highly increased mortality compared to APP23/Cnr1-/+ and APP23/Cnr1+/+ mice. Deletion of Cnr1 affects APP biochemistry, leading to a reduced amyloid plaque load and reduced inflammation. Despite that, APP23/Cnr1-/- mice displayed decreased learning and memory abilities. We will now analyze the regulatory role of CB1 receptors on the APP biochemistry in young and in the surviving old animals and employ in vitro models to study the signal transduction. To address the unexpected high mortality of the APP23/Cnr1-/- mice without an overt reason, we aim to decipher the cause of early death by focusing on potential key players and mechanisms of cell death including deficits in myelination, oxidative stress and the macroautophagy pathway. Therefore, we will investigate the expression of myelin basic protein as well as of myelin oligodendrocyte glycoprotein and 2',3'-cyclic nucleotide 3'- phosphodiesterase in young APP23/Cnr1-/- mice. In addition, we will compare the pathways of macroautophagy and protein degradation (e.g. LC3, p62, WIPI1, ubiquitin) and protein homeostasis in young and adult animals of all genotypes. In addition, we plan a detailed anatomical analysis of the animals, which have died prematurely in order to identify potential pathological abnormalities that indicate the cause of death.
DFG-Verfahren
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