A connection between the mitochondrial permeability transition pore, autophagy, and cerebral amyloidogenesis.
In a drug reprofiling attempt, we explored novel neuroprotective properties of 4-azasteroids by synthesizing chemical affinity tags capturing adenine nucleotide translocator-1, as a potential target. Dutasteride inhibits the mitochondrial transition pore and induces an increase of autophagosomal structures in human cell lines. In vivo, a surprising reduction of the beta-amyloid plaque load in a model for cerebral amyloidosis appears to connect release of neurotoxic peptides, mitochondrial apoptosis and autophagy.
Soskić
Vukić
V
ProteoSys AG, Carl Zeiss Strasse 51, D-55129 Mainz, Germany.
Klemm
Martina
M
Proikas-Cezanne
Tassula
T
Schwall
Gerhard P
GP
Poznanović
Slobodan
S
Stegmann
Werner
W
Groebe
Karlfried
K
Zengerling
Helmut
H
Schoepf
Rainer
R
Burnet
Michael
M
Schrattenholz
André
A
D016229:Amyloid beta-Peptides / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000686:Amyloidosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D001378:Azasteroids / Q000494:pharmacology*; D001927:Brain Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D000068538:Dutasteride; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018120:Finasteride / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000226:Mitochondrial ADP, ATP Translocases / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D016202:N-Methylaspartate / Q000494:pharmacology; D019579:Neocortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D058225:Plaque, Amyloid / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011190:Potassium Cyanide / Q000494:pharmacology; D053763:Presenilins / Q000235:genetics; D012737:Sex Factors; D013739:Testosterone / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001378:Azasteroids; D004791:Enzyme Inhibitors; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D018696:Neuroprotective Agents; D053763:Presenilins; D013739:Testosterone; D018120:Finasteride; D016202:N-Methylaspartate; D000226:Mitochondrial ADP, ATP Translocases; D011190:Potassium Cyanide; D000068538:Dutasteride