Nicholson and Ferreira’s new findings provide an important advance in our understanding of why high cholesterol levels may increase the vulnerability of neurons to dysfunction and death in Alzheimer disease. Previous studies in my laboratory and other laboratories had shown that Aβ can damage neurons by a mechanism involving membrane-associated oxidative stress and consequent perturbation of membrane proteins involved in the maintenance of cellular calcium homeostasis. As a result, calcium levels inside the neurons may rise excessively, resulting in damage to synapses and cell death. In addition, Ferreira and colleagues had previously provided evidence that the microtubule-associated protein tau is cleaved by calcium-activated proteases to generate a 17 kDa tau fragment that may itself adversely affect neurons.
In the present study, Nicholson and Ferreira manipulated and measured levels of cholesterol, tau proteolysis, and intracellular calcium levels
in cultured hippocampal neurons exposed to Aβ. They found that when
cholesterol levels are elevated, the neurons are more...