A buildup of amyloid beta proteins in the brain could cause good proteins to go bad, resulting in the formation of rod-like aggregates within neurons that leads to Alzheimer’s disease, according to research by a Colorado State University biochemistry professor.
The discovery provides new information on possible causes of Alzheimer’s disease and a mechanism for its progression, and it deepens scientists’ understanding of the neurological disease, which has no cure.
"These are normal proteins gone bad – it’s not that they’ve altered their structure, it’s a protein complex that is initially beneficial to the neuron when it forms but which becomes harmful if it is not removed within a short time after its formation," said Jim Bamburg, a member of Colorado State’s faculty since 1971. "This is a completely new paradigm for what might be the actual cause of the loss of neuronal connections (synapses) in Alzheimer’s disease."
Bamburg’s research interests have focused on neuronal cell biology, especially on a protein known as actin depolymerizing factor, or ADF, which he discovered during his first sabbatical leave in Cambridge, UK, in 1979. He is considered the world expert on ADF, and his papers have been cited more than 5,500 times.
Bamburg’s team – in the Department of Biochemistry and Molecular Biology, College of Natural Sciences – recently discovered that the presence of amyloid beta in brains leads to the rod-like aggregate formation in a sensitive subpopulation of neurons. Rod formation is prevalent in neurons within the brain’s hippocampus, where learning and memory occur.
Bamburg’s research on Alzheimer’s disease was initially funded in 2001 by a grant from the Alzheimer’s Foundation and more recently by a grant from the National Institute of Neurological Diseases and Stroke within the National Institutes of Health. The latter grant was recently renewed until 2010 for $1.2 million.
Dennis Selkoe, Vincent and Stella Coates Professor of Neurologic Diseases in the Department of Neurology at Harvard Medical School, has just begun a partnership with Bamburg.
"He does beautiful work," Selkoe said. "I like what he’s found in terms of the amyloid beta protein causing buildup of the cofilin rods. It is a very nice approach and very careful work."
The Colorado State discovery means scientists can begin to look at how to prevent the rods from forming. They still don’t know whether the existence of rods leads to an increase in production of amyloid beta proteins, causing the cycle to continue, Bamburg said.
"If rod formation generates more amyloid beta and this leads to more rod formation, we can begin to look at mechanisms to prevent rods from accumulating and perhaps even ways to eliminate rods that have formed," Bamburg said.
"Everything seems to be there for the production and processing of amyloid beta. Is it building up? Is it assembling into something more toxic that could lead to more A-beta? Is it the structure or the amount that’s important? These are all questions that drive our current research but which haven’t been fully answered," he said.
Individual cells have the power to migrate by assembling filaments of actin- one of the major proteins in muscle. Those filaments push the membrane forward like stretching a balloon. Actin depolymerizing factor (ADF) keeps the subunits of actin treadmilling (adding onto one end and coming off the other end), a process that is energy dependent and which can do work. Under stress, as energy declines, the sequestering of ADF into actin-containing rods lowers the actin filament treadmilling and conserves the cells chemical energy stores for other uses. Prolonged energy depletion leads to rods that become irreversible, leading to the loss of synaptic connections.