β-Amyloid (Aβ) 1–42, implicated in the pathogenesis of Alzheimer's disease, forms an oligomeric complex that binds copper at a CuZn superoxide dismutase-like binding site. Aβ·Cu complexes generate neurotoxic H₂O₂ from O₂ through Cu²⁺ reduction, but the reaction mechanism has been unclear. We now report that Aβ1–42, when binding up to 2 eq of Cu²⁺, generates the H₂O₂catalytically by recruiting biological reducing agents as substrates under conditions where the Cu²⁺ or reducing agents will not form H₂O₂ themselves. Cholesterol is an important substrate for this activity, as are vitamin C,l-DOPA, and dopamine (V _maxfor dopamine = 34.5 nm/min, K _m = 8.9 μm). The activity was inhibited by anti-Aβ antibodies, Cu²⁺ chelators, and Zn²⁺. Toxicity of Aβ in neuronal culture was consistent with catalytic H₂O₂ production. Aβ was not toxic in cell cultures in the absence of Cu²⁺, and dopamine (5 μm) markedly exaggerated the neurotoxicity of 200 nm Aβ1–42·Cu. Therefore, microregional catalytic H₂O₂ production, combined with the exhaustion of reducing agents, may mediate the neurotoxicity of Aβ in Alzheimer's disease, and inhibitors of this novel activity may be of therapeutic value.

Brain acetylcholinesterase (AChE) forms stable complexes with amyloid-β peptide (Aβ) during its assembly into filaments, in agreement with its colocalization with the Aβ deposits of Alzheimer’s brain. The association of the enzyme with nascent Aβ aggregates occurs as early as after 30 min of incubation. Analysis of the catalytic activity of the AChE incorporated into these complexes shows an anomalous behavior reminiscent of the AChE associated with senile plaques, which includes a resistance to low pH, high substrate concentrations, and lower sensitivity to AChE inhibitors. Furthermore, the toxicity of the AChE–amyloid complexes is higher than that of the Aβ aggregates alone. Thus, in addition to its possible role as a heterogeneous nucleator during amyloid formation, AChE, by forming such stable complexes, may increase the neurotoxicity of Aβ fibrils and thus may determine the selective neuronal loss observed in Alzheimer’s brain.

Alzheimer disease is a progressive neurodegenerative brain disorder that leads to major debilitating cognitive deficits. It is believed that the alterations capable of causing brain circuitry dysfunctions have a slow onset and that the full blown disease may take several years to develop. Therefore, it is important to understand the early, asymptomatic, and possible reversible states of the disease with the aim of proposing preventive and disease-modifying therapeutic strategies. It is largely unknown how amyloid beta-peptide (A beta), a principal agent in Alzheimer disease, affects synapses in brain neurons. In this study, we found that similar to other pore-forming neurotoxins, A beta induced a rapid increase in intracellular calcium and miniature currents, indicating an enhancement in vesicular transmitter release. Significantly, blockade of these effects by low extracellular calcium and a peptide known to act as an inhibitor of the A beta-induced pore prevented the delayed failure, indicating that A beta blocks neurotransmission by causing vesicular depletion. This new mechanism for A beta synaptic toxicity should provide an alternative pathway to search for small molecules that can antagonize these effects of A beta.

Copper is critical for the Central Nervous System (CNS) development and function. In particular, different studies have shown the effect of copper at brain synapses, where it inhibits Long Term Potentation (LTP) and receptor pharmacology. Paradoxically, according to recent studies copper is required for a normal LTP response. Copper is released at the synaptic cleft, where it blocks glutamate receptors, which explain its blocking effects on excitatory neurotransmission. Our results indicate that copper also enhances neurotransmission through the accumulation of PSD95 protein, which increase the levels of AMPA receptors located at the plasma membrane of the post-synaptic density. Thus, our findings represent a novel mechanism for the action of copper, which may have implications for the neurophysiology and neuropathology of the CNS. These data indicate that synaptic configuration is sensitive to transient changes in transition metal homeostasis. Our results suggest that copper increases GluA1 subunit levels of the AMPA receptor through the anchorage of AMPA receptors to the plasma membrane as a result of PSD-95 accumulation. Here, we will review the role of copper on neurotransmission of CNS neurons. In addition, we will discuss the potential mechanisms by which copper could modulate neuronal proteostasis (“neuroproteostasis”) in the CNS with focus in the Ubiquitin Proteasome System, which is particularly relevant to neurological disorders such Alzheimer’s disease (AD) where copper and protein dyshomeostasis may contribute to neurodegeneration. An understanding of these mechanisms may ultimately lead to the development of novel therapeutic approaches to control metal and synaptic alterations observed in AD patients.