Copper Chelator Induced Efficient Episodic Memory Recovery in a Non-Transgenic Alzheimer’s Mouse Model

Abstract

Alzheimer’s disease (AD) is a neurodegenerative syndrom involving many different biological parameters, including the accumulation of copper metal ions in Aβ amyloid peptides due to a perturbation of copper circulation and homeostasis within the brain. Copper-containing amyloids activated by endogenous reductants are able to generate an oxidative stress that is involved in the toxicity of abnormal amyloids and contribute to the progressive loss of neurons in AD. Since only few drugs are currently available for the treatment of AD, we decided to design small molecules able to interact with copper and we evaluated these drug-candidates with non-transgenic mice, since AD is mainly an aging disease, not related to genetic disorders. We created a memory deficit mouse model by a single icv injection of Aβ1–42 peptide, in order to mimic the early stage of the disease and the key role of amyloid oligomers in AD. No memory deficit was observed in the control mice with the antisense Aβ42-1 peptide. Here we report the capacity of a new copper-specific chelating agent, a bis-8-aminoquinoline PA1637, to fully reverse the deficit of episodic memory after three weeks of treatment by oral route on non-transgenic amyloid-impaired mice. Clioquinol and memantine have been used as comparators to validate this fast and efficient mouse model.

How Zn can impede Cu detoxification by chelating agents in Alzheimer's disease: a proof-of-concept study

“…Later the same group showed that a clioquinol derivative named PBT2 also improved the cognitive performance in AD model mice. 15 More recent studies on the impact of chelators on AD model mice include the studies of bis-8-aminoquinoline derivatives 16 and of the so-called metamorphosizers. 17 However, these seminal studies did not address the question of which metal is targeted by the chelators.…”

A newly designed molecule J2326 for Alzheimer's disease disaggregates amyloid fibrils and induces neurite outgrowth

“…Although lacking higher zinc binding activity, J2326 has metal selectivity toward to zinc. This make J2326 different from clioquinol and PBT2, of which both liberate either copper or zinc ions trapped by amyloid (Ferrada et al, 2007;Barnham and Bush, 2014), and also unlike PA1637, which is copper-specific (Ceccom et al, 2012;Nguyen et al, 2014); and lead J2326 to display an effective zinc-dependent fAb disaggregation. Apart from zincdependent effect, J2326 also showed zinc-independent anti-fAb effect (Figs.…”

“…1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 The fAb-driven neurodegeneration cannot be reversed by currently available therapies, which include acetylcholinesterase (AChE) inhibitors and NMDA antagonists, but these can only control the symptoms by affecting the function of brain neurotransmitters and slowing cognitive decline. In recent years, amyloid based strategies are likely to show potency against AD; however, numerous clinical trials of these types of agents, for example AN1792 (Ab-mediated immunotherapy reported by Sperling et al, 2011), tramiprosate (anti-Ab aggregating agent reported by SantaMaria et al, 2007), tarenflurbil (Ab-lowering agent reported by Wan et al, 2009), clioquinol and PBT2 and PA1637 (chelating agents reported by Cherny et al, 1999;Barnham et al, 2003, and Ceccom et al, 2012 and semagacestat (secretase inhibitor reported by Extance, 2010), have been discontinued because of either safety reasons or the absence of clinically significant benefits. Another strategy with a long history being a potential therapy for AD is neurotrophic supplementation by giving especially nerve growth factor (NGF).…”

Ionophoric polyphenols selectively bind Cu2+, display potent antioxidant and anti-amyloidogenic properties, and are non-toxic toward Tetrahymena thermophila

“…This would allow to compete with A for metal binding (A forms 1:1 complexes with Cu 2+ with LogK a values in the range 8-10, depending on experimental conditions 17,54 ), but not with metalloenzymes, therefore, resulting in a combination that could promote restoration of ionic balance rather than total removal of metal ions. 55 Given the active role of Cu 2+ in promoting A aggregation and ROS production, compounds 1-5 were studied spectrophotometrically and compared to CQ and 59 Because of its low metal binding affinity, literature argues that CQ has the potential not to interfere with intracellular metalbinding enzymes 57 and, therefore, CQ is claimed to be able to remove metal ions from A and redistribute them within the brain regions where they can promote synaptic function. 55 However, severe myelo-optic acute neuropathy on patients treated with CQ has been associated to lack of tissue and/or ion selectivity and, most especially, to the ability to chelate Zn 2+ .…”