Subject(s)
Alzheimer Disease/drug therapy , Amyloid/metabolism , Coordination Complexes/chemistry , Platinum/chemistry , Amyloid/antagonists & inhibitors , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Animals , Brain/metabolism , Cell Survival/drug effects , Coordination Complexes/therapeutic use , Coordination Complexes/toxicity , Disease Models, Animal , Mice , Mice, Transgenic , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/metabolism , Quinolines/chemistry , Spectrometry, Mass, Matrix-Assisted Laser Desorption-IonizationABSTRACT
Cognitive decline in Alzheimer's disease (AD) involves pathological accumulation of synaptotoxic amyloid-beta (Abeta) oligomers and hyperphosphorylated tau. Because recent evidence indicates that glycogen synthase kinase 3beta (GSK3beta) activity regulates these neurotoxic pathways, we developed an AD therapeutic strategy to target GSK3beta. The strategy involves the use of copper-bis(thiosemicarbazonoto) complexes to increase intracellular copper bioavailability and inhibit GSK3beta through activation of an Akt signaling pathway. Our lead compound Cu(II)(gtsm) significantly inhibited GSK3beta in the brains of APP/PS1 transgenic AD model mice. Cu(II)(gtsm) also decreased the abundance of Abeta trimers and phosphorylated tau, and restored performance of AD mice in the Y-maze test to levels expected for cognitively normal animals. Improvement in the Y-maze correlated directly with decreased Abeta trimer levels. This study demonstrates that increasing intracellular copper bioavailability can restore cognitive function by inhibiting the accumulation of neurotoxic Abeta trimers and phosphorylated tau.
Subject(s)
Amyloid beta-Peptides/drug effects , Copper/pharmacology , tau Proteins/drug effects , Alzheimer Disease/drug therapy , Amyloid beta-Peptides/metabolism , Animals , Brain/metabolism , Cognition/drug effects , Copper/pharmacokinetics , Copper/therapeutic use , Dimerization , Disease Models, Animal , Glycogen Synthase Kinase 3/antagonists & inhibitors , Glycogen Synthase Kinase 3 beta , Glycogen Synthase Kinases/antagonists & inhibitors , Maze Learning , Mice , Mice, Inbred C57BL , Mice, Transgenic , Organometallic Compounds/pharmacokinetics , Phosphorylation/drug effects , Proto-Oncogene Proteins c-akt/metabolism , tau Proteins/metabolismABSTRACT
As a disease-modifying approach for Alzheimer's disease (AD), clioquinol (CQ) targets beta-amyloid (Abeta) reactions with synaptic Zn and Cu yet promotes metal uptake. Here we characterize the second-generation 8-hydroxy quinoline analog PBT2, which also targets metal-induced aggregation of Abeta, but is more effective as a Zn/Cu ionophore and has greater blood-brain barrier permeability. Given orally to two types of amyloid-bearing transgenic mouse models of AD, PBT2 outperformed CQ by markedly decreasing soluble interstitial brain Abeta within hours and improving cognitive performance to exceed that of normal littermate controls within days. Nontransgenic mice were unaffected by PBT2. The current data demonstrate that ionophore activity, inhibition of in vitro metal-mediated Abeta reactions, and blood-brain barrier permeability are indices that predict a potential disease-modifying drug for AD. The speed of recovery of the animals underscores the acutely reversible nature of the cognitive deficits associated with transgenic models of AD.
Subject(s)
Alzheimer Disease , Amyloid beta-Peptides/metabolism , Cognition/drug effects , Hydroxyquinolines/therapeutic use , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Alzheimer Disease/physiopathology , Amyloid beta-Peptides/drug effects , Amyloid beta-Protein Precursor/genetics , Analysis of Variance , Animals , Behavior, Animal , Cell Line, Tumor , Clioquinol , Copper/pharmacology , Disease Models, Animal , Hippocampus/drug effects , Hippocampus/physiopathology , Humans , In Vitro Techniques , Long-Term Potentiation/drug effects , Maze Learning , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neuroblastoma , Peptide Fragments/metabolism , Presenilin-1/genetics , Zinc/pharmacologyABSTRACT
Dementia with Lewy bodies (DLB) is pathologically characterized by the presence of alpha-synuclein-containing Lewy bodies within the neocortical, limbic, and paralimbic regions. Like Alzheimer's disease (AD), Abeta plaques are also present in most DLB cases. The contribution of Abeta to the development of DLB is unclear. [11C]-Pittsburgh compound B ([11C]-PIB) is a thioflavin-T derivative that has allowed in vivo Abeta burden to be quantified using positron emission tomography (PET). [11C]-PIB PET studies have shown similar high cortical [11C]-PIB binding in AD and DLB subjects. To establish the potential binding of PIB to alpha-synuclein in DLB patients, we characterized the in vitro binding of PIB to recombinant human alpha-synuclein and DLB brain homogenates. Analysis of the in vitro binding studies indicated that [3H]-PIB binds to alpha-synuclein fibrils but with lower affinity than that demonstrated/reported for Abeta(1-42) fibrils. Furthermore, [3H]-PIB was observed to bind to Abeta plaque-containing DLB brain homogenates but failed to bind to DLB homogenates that were Abeta plaque-free ("pure DLB"). Positive PIB fluorescence staining of DLB brain sections colocalized with immunoreactive Abeta plaques but failed to stain Lewy bodies. Moreover, image quantification analysis suggested that given the small size and low density of Lewy bodies within the brains of DLB subjects, any contribution of Lewy bodies to the [11C]-PIB PET signal would be negligible. These studies indicate that PIB retention observed within the cortical gray matter regions of DLB subjects in [11C]-PIB PET studies is largely attributable to PIB binding to Abeta plaques and not Lewy bodies.
