Diagnostics & Imaging Week
Alzheimer's is a neurodegenerative disease, but one idea is that neurons degenerate because of reduced blood flow to the brain. In 2007, researchers from the University of Rochester (Rochester, New York) published data showing that two cardiovascular proteins, serum response factor or SRF, and myocardin, are overexpressed in tissues from patients with late–stage Alzheimer's disease.
Now, the authors of that paper have published a follow–up report that details the mechanism by which the two proteins do their damage: they set in motion a chain of molecular events that leaves the brain unable to clear toxic amyloid–beta. And another paper shows how the reduced glucose supply that is one consequence of decreased blood flow can trigger the formation of those plaques.
The first paper is published in the Dec 21 issue of Nature Cell Biology. In a nutshell, its authors find that high levels of SRF and myocardin lead to high levels of the regulatory protein SREBP2. This in turn reduces levels of low–density lipoprotein related protein 1 or LRP–1, which normally clears amyloid–beta from the brain.
Compared to vascular smooth muscle from healthy adults, cells from patients with Alzheimer's disease had about five times as much myocardin and four times as much SRF, about five times as much SREBP2, and about 60% less LRP–1. Those differences translated into a reduced ability to remove amyloid beta. Cells taken from Alzheimer's patients removed only about a third as much amyloid–beta as cells from healthy adults.
Reducing SRF levels to normal levels led to increased amyloid–beta clearance, while increasing levels of either SRF of myocardin in healthy cells reduced their ability to clear amyloid by about two–thirds.
The same relationships between the molecular players held true in animal studies. Healthy mice with increased levels of SRF or myocardin had about twice as much SREBP2 in their smooth muscle cells in the brain's blood vessels. They also had starkly reduced levels of LRP–1, and higher levels of amyloid beta both in their blood vessels in their brain tissue.
When the team reduced SRF and myocardin in mice that are usually prone to developing Alzheimer's disease, those mice had less SREBP2, more LRP–1, and a 50% reduction in amyloid beta in their blood vessels.
Co–authors on the paper come from the University of Rochester, Stony Brook University, and Socratech, a spin–out from the University of Rochester of which senior author Berislav Zlokovic is co–founder and chief scientific officer.
In Alzheimer's disease, not only is amyloid beta clearance reduced, but its production is increased. Increased expression of the BACE1 gene leads to high levels of the enzyme that cleaves amyloid precursor protein, which is ultimately processed into plaque–forming beta amyloid.
In the Dec 26 issue of Neuron, researchers report findings that link low levels of glucose in the brain to the expression of a transcription factor that increases the levels of BACE1 in the brain.
Using cell culture experiments, the researchers – who are from Northwestern University's Feinberg School of Medicine, Rush University, Ludwig–Maximilians–University in Germany and Catholic University Leiden in Belgium – found that low levels of glucose trigger the phosphorylation of the translation factor elF–2 alpha, which in turn led to increased translation of BACE1 and from there, to increased levels of amyloid–beta.
Blocking elF–2 alpha phosphorylation prevented the increases in response to reduced energy.
The team concludes that their results "strongly suggest that [eIF–2 alpha] phosphorylation increases BACE1 levels and causes [Abeta] overproduction, which could be an early, initiating molecular mechanism" in sporadic Alzheimer's disease.