Trace amounts of copper in water induce β-amyloid plaques and learning deficits in a rabbit model of Alzheimer's disease

TLDR

Cholesterol and copper are implicated in Alzheimer’s disease, with trace copper in drinking water potentially impairing Aβ clearance at the blood–brain interface and, together with high cholesterol, promoting Aβ accumulation that affects learning and memory. In cholesterol‑fed rabbits, adding 0.12 ppm copper to drinking water caused β‑amyloid plaque‑like deposits in the hippocampus and temporal lobe, slowed performance on a trace conditioning task while leaving simpler conditioning intact, and the animals displayed at least 12 AD‑like pathological markers, validating the model.

Abstract

Despite the crucial role played by cholesterol and copper in nutrition and normal brain function, recent evidence indicates that they may both be important factors in the etiology of Alzheimer's disease (AD). Here we provide critical evidence for the role of cholesterol and copper in AD by showing that the addition of trace amounts of copper (0.12 ppm) to water given to cholesterol-fed rabbits can induce β-amyloid (Aβ) accumulation, including senile plaque-like structures in the hippocampus and temporal lobe, and can significantly retard the ability of rabbits to learn a difficult trace conditioning task. The Aβ deposits do not affect the ability of rabbits to detect or respond to the training stimuli nor to learn a simpler delay conditioning task. Trace amounts of copper in drinking water may influence clearance of Aβ from the brain at the level of the interface between the blood and cerebrovasculature and combined with high cholesterol may be a key component to the accumulation of Aβ in the brain, having a significant impact on learning and memory. Cholesterol-fed rabbits have at least 12 pathological markers seen in AD, suggesting that the cholesterolfed rabbit is a good animal model for studying AD.