Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Alzheimer Disease / complications*
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Alzheimer Disease / genetics
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Alzheimer Disease / metabolism
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Alzheimer Disease / pathology
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Amyloid beta-Peptides / metabolism*
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Amyloid beta-Protein Precursor / genetics
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Analysis of Variance
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Animals
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Astrocytes / drug effects
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Astrocytes / metabolism
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Astrocytes / pathology
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Cell Count / methods
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Disease Models, Animal
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Enzyme-Linked Immunosorbent Assay / methods
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Glial Fibrillary Acidic Protein / metabolism
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Hippocampus / metabolism
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Humans
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Indoles / pharmacology
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Indoles / therapeutic use*
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Maze Learning / drug effects
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Memory Disorders / drug therapy*
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Memory Disorders / etiology*
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Mice
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Mice, Transgenic
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Microglia / drug effects
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Microglia / metabolism
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Microglia / pathology
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Neocortex / metabolism
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Neuropsychological Tests
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Oximes / pharmacology
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Oximes / therapeutic use*
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Peptide Fragments / metabolism*
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Presenilin-1 / genetics
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Synaptophysin / metabolism
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tau Proteins / metabolism
Substances
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Glial Fibrillary Acidic Protein
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Indoles
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Oximes
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PSEN1 protein, human
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Peptide Fragments
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Presenilin-1
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Synaptophysin
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amyloid beta-protein (1-42)
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indirubin-3'-monoxime
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tau Proteins