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Cognitive decline in Alzheimer's disease (AD) involves pathological accumulation of synaptotoxic amyloid-β (Aβ) oligomers and hyperphosphorylated tau. Because recent evidence indicates that glycogen synthase kinase 3β (GSK3β) activity regulates these neurotoxic pathways, we developed an AD therapeutic strategy to target GSK3β. The strategy involves the use of copper- bis (thiosemicarbazonoto) complexes to increase intracellular copper bioavailability and inhibit GSK3β through activation of an Akt signaling pathway. Our lead compound Cu II (gtsm) significantly inhibited GSK3β in the brains of APP/PS1 transgenic AD model mice. Cu II (gtsm) also decreased the abundance of Aβ 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 Aβ trimer levels. This study demonstrates that increasing intracellular copper bioavailability can restore cognitive function by inhibiting the accumulation of neurotoxic Aβ trimers and phosphorylated tau.

Robert A. Cherny, Paul A. Adlard, David I. Finkelstein, Elisabeth Gautier, Penny Huggins, Jack Parsons, Craig W. Ritchie, Elysia Robb, Mikhalina Cortes, Irene Volitakis, Xiang Liu, Jeffrey P. Smith, Keyla Perez, Katrina Laughton, Qiao-Xin Li, Susan A. Charman, Joseph A. Nicolazzo, Simon Wilkins, Karolina Deleva, Gaik Kok, Roberto Cappai, Rudi E. Tanzi, Colin L. Masters, Kevin J. Barnham, Ashley I. Bush, The Mental Health Research Institute of Victoria & The University of Melbourne, Parkville, VIC, Australia; MHRI & The University of Melbourne, Parkville, Australia; Prana Biotechnology Ltd, Parkville, Australia; Imperial College London, London, United Kingdom; MHRI, Parkville, Australia; The University of Melbourne, Parkville, Australia; Centre for Drug Candidate Optimisation, Parkville, Australia; Bio 21 Institute, The University of Melbourne, Parkville, Australia; Genetics & Aging Research Unit, MGH, Boston, MA, USA. Contact e-mail: rcherny@mhri.edu.au

Dementia with Lewy bodies (DLB) is pathologically characterized by the presence of α-synuclein-containing Lewy bodies within the neocortical, limbic, and paralimbic regions. Like Alzheimer's disease (AD), Aβ plaques are also present in most DLB cases. The contribution of Aβ to the development of DLB is unclear. [11C]-Pittsburgh compound B ([11C]-PIB) is a thioflavin-T derivative that has allowedin vivoAβ 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 α-synuclein in DLB patients, we characterized thein vitrobinding of PIB to recombinant human α-synuclein and DLB brain homogenates. Analysis of thein vitrobinding studies indicated that [3H]-PIB binds to α-synuclein fibrils but with lower affinity than that demonstrated/reported for Aβ1–42fibrils. Furthermore, [3H]-PIB was observed to bind to Aβ plaque-containing DLB brain homogenates but failed to bind to DLB homogenates that were Aβ plaque-free (“pure DLB”). Positive PIB fluorescence staining of DLB brain sections colocalized with immunoreactive Aβ 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 Aβ plaques and not Lewy bodies.

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.