Indirubin-3'-monoxime rescues spatial memory deficits and attenuates beta-amyloid-associated neuropathology in a mouse model of Alzheimer's disease.
Indirubin and its derivatives have been shown to possess potent inhibitory effects on cyclin-dependent protein kinase 5 and glycogen synthase kinase 3beta, two protein kinases involved in abnormal hyperphosphorylation of tau and amyloid precursor protein processing/beta-amyloid (Abeta) production. Here, we showed that systemic treatment of APP and presenilin 1 (PS1) transgenic mice, a robust Alzheimer's disease (AD) mouse model, with indirubin-3'-monoxime (IMX; 20mg/kg; 3 times weekly), for as little as 2months, significantly attenuated spatial memory deficits. This was accompanied by a marked decrease in several AD-like phenotypes, including Abeta deposition, tau hyperphosphorylation, accumulation of activated microglia and astrocytes around Abeta plaques, and loss of synaptophysin immunoreactivity. These findings suggest that IMX is a potential therapeutic agent to combat AD.
Ding
Yun
Y
Department of Veterans Affairs Medical Center, Richmond, VA 23249, USA.
Qiao
Aimin
A
Fan
Guo-Huang
GH
D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002452:Cell Count / Q000379:methods; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000188:drug therapy* / Q000209:etiology*; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019579:Neocortex / Q000378:metabolism; D009483:Neuropsychological Tests; D010091:Oximes / Q000494:pharmacology / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics; D016708:Synaptophysin / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D005904:Glial Fibrillary Acidic Protein; D007211:Indoles; D010091:Oximes; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D016708:Synaptophysin; C075222:amyloid beta-protein (1-42); C474021:indirubin-3'-monoxime; D016875:tau Proteins