The road to LOAD: late-onset Alzheimer's disease and a possible way to block it.
The ageing brain becomes increasingly less able to destroy or eject toxic amyloid (A) beta42 peptide byproducts of normal neuronal activity that consequently accumulate to induce Alzheimer's disease (AD). Therefore, the various components of the Abeta-clearing machinery are prime targets for AD therapeutics. In this connection, there are reports that taking statins to lower circulating cholesterol to prevent cardiovascular disease can also prevent late-onset AD (LOAD) the most common form of the disease. However, it seems unlikely that statins would prevent LOAD by lowering the very long-lived brain cholesterol that is controlled independently from the very much shorter-lived circulating cholesterol. In fact, reducing the ability of the brain astrocytes to make cholesterol for their closely associated neuron clients' synaptogenesis could damage the brain rather than protect it. However, a plausible way statins might prevent LOAD is to target a main component of the clearance machinery, low-density lipoprotein receptor-related protein 1 (LRP1), the brain's powerful Abeta-efflux driver. This is indicated by a reported ability of micromolar concentrations of lovastatin and simvastatin to strongly stimulate brain vascular endothelial cells to make this Abeta ejector. Therefore, if this holds up, taking a statin over the years would prevent the normal decline of LRP1 in the ageing brain and a LOAD-driving accumulation of Abeta.
Whitfield
James F
JF
D017668:Age of Onset; D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000502:physiology
D016229:Amyloid beta-Peptides; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D010446:Peptide Fragments; C442220:amyloid beta-protein (2-42); D002784:Cholesterol