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Projekt Druckansicht

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

Fachliche Zuordnung Biologische Psychiatrie
Förderung Förderung von 2008 bis 2014
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 42860621
 
Erstellungsjahr 2017

Zusammenfassung der Projektergebnisse

Established therapy strategies of Alzheimer's Disease (AD), using acetylcholine-esterase inhibitors, NMDA-antagonists and psychotropic drugs are only targeting the treatment of the patients syndromes. These treatment approaches are able to delay the progression of the disease by a few years at best. Most experimental treatment strategies, which have been evaluated in recent clinical studies are focusing on the elevated clearance of the potentially toxic Aß peptides, whereby the pharmacological development has been concentrated on drugs inhibiting the proteases involved in the amyloidogenic processing of APP. All of these inhibitors, which proceeded up to phase III clinical trials failed at the end, because of severe side effects in patients. Based on the data of this study, one might argue that inhibiting CB1 could be used as an alternative treatment for AD, because the reduction of CB1 activity decreases APP processing and thereby the levels of Aß peptides. However, the reduced gliosis and decreased APP processing in APP23/CB1-/- animals compared to APP23 animals did not correlate with enhanced cognitive abilities, but with a decline in spacial learning. Data raised in these studies show, that CB1 is also influencing the nonamyloidogenic processing of APP. Thus, a treatment strategy of AD based on CB1 activity inhibition and thereby the reduction of amyloidogenic APP-processing might be unrewarding as the neuroprotective, non-amyloidogenic processing of APP is decreased at the same time. The reduced amyloidogenic APP-processing in APP23/CB1-/- mice cannot be causative for the detrimental phenotype of those animals. A disturbance in the autophagosomal/lysosomal system might be an alternative explanation for the impact of the CB1 depletion in the genetic background of the APP23 mice. Various scientific reports show, that this degradation system is altered by the pathological changes during AD-progression and some claim that CB1 activity has an influence on lysosomal degradation. Thereby, the possible influence of the CB1 on the autophagic flux was investigated in these studies. In the cellular model systems utilized, CB1 activity specifically modulated the formation of autophagic vesicles, as the lysosomal activity and the activity of the ubiquitin-proteasom system (UPS) are not altered by CB1 knockdown. Interestingly, the modulation of the autophagic flux by CB1 is independent of the two canonical protein-complexes (mTOR- and BECLIN1-complex) regulating the induction of autophagic vesicle formation. Thus, CB1 modulates the autophagic flux in a non-canonical fashion, whereas the signal-pathway has not been revealed, so far. The precise molecular mechanism connecting CB1 signaling to the induction of autophagic vesicle formation, should be subjected to further investigations in the future.

Projektbezogene Publikationen (Auswahl)

  • Protein homeostasis, aging and Alzheimer's disease. Mol. Neurobiol 46 (2012) 41–54
    T. Morawe, C. Hiebel, A. Kern, C. Behl
    (Siehe online unter https://doi.org/10.1007/s12035-012-8246-0)
  • Cannabinoid receptor 1 deficiency in a mouse model of Alzheimer's disease leads to enhanced cognitive impairment despite of a reduction in amyloid deposition. Neurobiol. Aging 34 (2013) 2574– 2584
    C. Stumm and C. Hiebel, R. Hanstein, M. Purrio, H. Nagel, A. Conrad, B. Lutz, C. Behl, A.B. Clement
    (Siehe online unter https://doi.org/10.1016/j.neurobiolaging.2013.05.027)
  • Cannabinoid receptor 1 modulates the autophagic flux independent of mTOR- and BECLIN1-complex. Journal of Neurochemistry (2014)
    C. Hiebel, T. Kromm, M. Stark, C. Behl
    (Siehe online unter https://doi.org/10.1111/jnc.12839)
  • The complex modulation of lysosomal degradation pathways by cannabinoid receptors 1 and 2. Life Sciences 138 (2015) 3-7
    C. Hiebel and C. Behl
    (Siehe online unter https://doi.org/10.1016/j.lfs.2015.03.020)
 
 

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