. Increased membrane cholesterol might render mature hippocampal neurons more susceptible to beta-amyloid-induced calpain activation and tau toxicity. J Neurosci. 2009 Apr 8;29(14):4640-51. PubMed.

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  1. 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 vulnerable to Aβ toxicity, and the increased vulnerability is associated with increased intracellular calcium levels and increased production of the 17 kDa tau fragment. Our previous findings indicated that the increased oxidative stress that occurs during aging and AD may itself perturb membrane cholesterol and sphingomyelin metabolism (Cutler et al., 2004). Collectively, the available data suggest that a self-propagating neurodegenerative cascade may occur in AD in which oxidative stress perturbs lipid metabolism, resulting in impaired calcium regulation and pathological changes in tau which, in turn, exacerbate oxidative stress and further disrupt cellular calcium homeostasis. Lowering cholesterol levels through dietary modifications, exercise, and statins may, therefore, stabilize cellular calcium homeostasis and so protect neurons against dysfunction and degeneration in aging and AD.

    View all comments by Mark Mattson