Increasing Cu bioavailability inhibits Aβ oligomers and tau phosphorylation

Abstract

Cognitive decline in Alzheimer's disease (AD) involves pathological accumulation of synaptotoxic amyloid-␤ (A␤) oligomers and hyperphosphorylated tau. Because recent evidence indicates that glycogen synthase kinase 3␤ (GSK3␤) activity regulates these neurotoxic pathways, we developed an AD therapeutic strategy to target GSK3␤. The strategy involves the use of copper-bis(thiosemicarbazonoto) complexes to increase intracellular copper bioavailability and inhibit GSK3␤ through activation of an Akt signaling pathway. Our lead compound Cu II (gtsm) significantly inhibited GSK3␤ in the brains of APP/PS1 transgenic AD model mice. Cu II (gtsm) also decreased the abundance of A␤ 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 A␤ trimer levels. This study demonstrates that increasing intracellular copper bioavailability can restore cognitive function by inhibiting the accumulation of neurotoxic A␤ trimers and phosphorylated tau.Alzheimer's disease ͉ bioinorganic chemistry ͉ glycogen synthase kinase ͉ therapeutic ͉ animal model A lzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by impaired cognitive performance and pathologically by cerebral deposition of extracellular amyloid plaques and intracellular neurofibrillary tangles. Amyloid plaques in AD contain aggregated forms of the 39-to 43-aa amyloid-␤ peptide (A␤) and A␤ is strongly implicated as a causative agent responsible for cognitive failure in AD. A diverse range of mechanisms for A␤ toxicity has been reported (1). A␤ is produced from the amyloid precursor protein (APP) (2-5) and readily aggregates to form insoluble, high-molecular-mass amyloid structures. Intermediates on the A␤ aggregation pathway, primarily low-molecular-mass oligomers such as dimers and trimers, exhibit the greatest neurotoxicity (6-8). In addition to A␤ oligomers, aberrantly phosphor ylated microtubuleassociated protein tau is also associated with cognitive decline in AD (9). Intracellular neurofibrillary tangles in the AD brain contain hyperphosphorylated tau, and A␤ induced cognitive deficits characteristic of AD transgenic mice are attenuated by decreasing levels of endogenous tau (10).It is now widely recognized that a truly effective therapeutic compound for treating AD needs to attenuate both the A␤-and tau-mediated pathologies. Recent positive outcomes for PBT2 in clinical and preclinical trials are therefore pertinent. Lannfelt et al.(11) demonstrated in phase IIa clinical trials that PBT2 lowers plasma A␤ levels and attenuates cognitive decline, and Adlard et al. (12) have shown that PBT2 decreases interstitial A␤ and phosphorylated tau in the brains of AD model mice. PBT2 is a secondgeneration 8-OH quinoline, which, unlike its predecessor clioquinol, lacks iodine and was selected for clinical development because of its easier chemical synthesis, higher solubility, and increased blood-brain barrier perme...

An impaired mitochondrial electron transport chain increases retention of the hypoxia imaging agent diacetylbis(4-methylthiosemicarbazonato)copper II

“…3 B and C). Increased phosphorylation of cell-signaling kinases after treating with bisðthiosemicarbazonatoÞCu II compounds is dependent on the relative Cu II ∕Cu I reduction potential of the compounds (28,29). Increased kinase phosphorylation in response to bisðthiosemicarbazonatoÞCu II treatment is therefore likely to involve intracellular dissociation of the compound giving rise to increased intracellular levels of bioavailable Cu.…”

Cellular Up-regulation of Nedd4 Family Interacting Protein 1 (Ndfip1) using Low Levels of Bioactive Cobalt Complexes

“…Changes to transition metal-ion homeostasis have been implicated in a number of neurodegenerative conditions and therapeutic approaches that target transition metal ion metabolism, specifically copper and zinc, have shown promise in the treatment of Alzheimer disease (1,32). For example, copper-bis(thiosemicarbazone) complexes such as Cu II (gtsm) can cross the blood-brain barrier and increase cellular metal ion bioavailability, leading to inhibition of glycogen synthase kinase 3␤ (GSK3␤), which ultimately results in degradation of A␤ and tau phosphorylation (1). In the present study, direct introduction of cobalt complex C3 into the adult mouse brain was efficient in increasing neuronal levels of Ndfip1.…”

“…For example, metals such as iron, copper, and cobalt can produce reactive oxygen species that lead to the activation of redox-sensitive transcription factors including NF-B, AP-1, and p53. Metals have also been suggested to affect the upstream regulatory components of the MAP kinase and the PI3K/Akt/mTor pathway (1,2). Thus the levels and regulation of metals in a cell can have a direct role on cell function and survival.…”

Biometals and Their Therapeutic Implications in Alzheimer's Disease

“…In transgenic mice overexpressing mutant APP, presenilin and tau, copper exposure accelerates tau hyperphosphorylation [193]. However, in mice that overexpress only APP and presenilin, copper delivery drugs have been shown to reduce GSK-3β-dependent tau phosphorylation [194].…”

“…The coppercontaining bis(thiosemicarbazone) compound Cu II GTSM, has been shown to lower Aβ levels, GSK3β activity, and phosphorylated tau levels in cell culture and APP/PS1 transgenic mice [194,219], which accompanied improved cognition in the Y-maze assay. A related compound, Cu II ATSM, was not beneficial to the APP/PS1 transgenic model of AD, but conferred neuroprotection in 4 animal models of PD [220], which is also complicated by copper deficiency [168].…”