TY - JOUR
T1 - Clioquinol and other hydroxyquinoline derivatives inhibit Aβ(1-42) oligomer assembly
AU - LeVine, Harry
AU - Ding, Qunxing
AU - Walker, John A.
AU - Voss, Randal S.
AU - Augelli-Szafran, Corinne E.
PY - 2009/11/6
Y1 - 2009/11/6
N2 - Soluble oligomeric amyloid-β (Aβ) species are toxic to many cell types and are a putative etiological factor in Alzheimer's disease. The NINDS-Custom Collection of 1040 drugs and biologically active compounds was robotically screened for inhibitors of Aβ oligomer formation with a single-site biotinylated Aβ(1-42) oligomer assembly assay. Several quinoline-like compounds were identified with IC50's <10 μM, including the antiprotozoal clioquinol that has been reported to have effects on metal ion metabolism. The 2-OH, 4-OH, and 6-OH quinolines do not block Aβ oligomer formation up to a concentration of 100 μM. Analogs of clioquinol have shown activity in reducing Aβ levels and improving behavioral deficits in mouse models of Aβ pathology. The inhibitory effects of clioquinol and other 8-OH quinoline derivatives on oligomer formation in vitro are unrelated to their chelating activity. Crosslinking studies suggest that clioquinol acts at the stage of trimer formation. These preliminary data may suggest that 8-OH quinolines have the potential for suppressing Aβ oligomer formation which should be considered when assessing the effects of these compounds in animal models and clinical trials.
AB - Soluble oligomeric amyloid-β (Aβ) species are toxic to many cell types and are a putative etiological factor in Alzheimer's disease. The NINDS-Custom Collection of 1040 drugs and biologically active compounds was robotically screened for inhibitors of Aβ oligomer formation with a single-site biotinylated Aβ(1-42) oligomer assembly assay. Several quinoline-like compounds were identified with IC50's <10 μM, including the antiprotozoal clioquinol that has been reported to have effects on metal ion metabolism. The 2-OH, 4-OH, and 6-OH quinolines do not block Aβ oligomer formation up to a concentration of 100 μM. Analogs of clioquinol have shown activity in reducing Aβ levels and improving behavioral deficits in mouse models of Aβ pathology. The inhibitory effects of clioquinol and other 8-OH quinoline derivatives on oligomer formation in vitro are unrelated to their chelating activity. Crosslinking studies suggest that clioquinol acts at the stage of trimer formation. These preliminary data may suggest that 8-OH quinolines have the potential for suppressing Aβ oligomer formation which should be considered when assessing the effects of these compounds in animal models and clinical trials.
KW - Amyloid
KW - Biotin
KW - Crosslinking
KW - ELISA
KW - PICUP
KW - Robotic screening
UR - http://www.scopus.com/inward/record.url?scp=70349142176&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=70349142176&partnerID=8YFLogxK
U2 - 10.1016/j.neulet.2009.08.002
DO - 10.1016/j.neulet.2009.08.002
M3 - Article
C2 - 19664688
AN - SCOPUS:70349142176
SN - 0304-3940
VL - 465
SP - 99
EP - 103
JO - Neuroscience Letters
JF - Neuroscience Letters
IS - 1
ER -