Jeffrey L. Noebels, M.D., Ph.D.
Waxing and waning periods of confusion, characteristic of people with Alzheimer's disease, have long puzzled physicians who treat patients with the disease.
Now, research by scientists at Baylor College of Medicine and the Gladstone Institute of Neurological Disease in San Francisco, Calif., may have identified the cause (http://www.gladstone.ucsf.edu/gladstone/site/gweb1/).
'Silent seizures' measured in the brains of mice genetically engineered to have a disease like Alzheimer's could mimic the periods of confusion seen in human sufferers of the disease, said Jeffrey Noebels, M.D., Ph.D., BCM professor of neurology, neuroscience and molecular and human genetics and a co-senior author of the report that appears in the journal Neuron. These seizures are related to cellular changes involving the excess accumulations of the protein amyloid beta, a material long thought to play a role in Alzheimer's.
"These seizures are not the typical epileptic seizures or convulsions that most people would recognize," said Noebels. "These episodes may be the reason that some people with advanced Alzheimer's disease have 'spells' of increased confusion. Further study of this mouse may offer new ways to prevent these episodes."
Noebels recorded electrical brain waves deep in the brain of these special mice in the Bluebird Circle Developmental Neurogenetics Laboratory at BCM (http://imgen.bcm.tmc.edu/molgen/facultyaz/noebels.html). He is the laboratory's director. The activity was detected in the brain's hippocampus, an area important in memory.
"This discovery has helped identify a new and potentially reversible neural mechanism that can explain the episodes of sudden severe confusion found in cases of advanced Alzheimer's disease," said Noebels.
"The cellular changes that give rise to this hyperexcitability appear slowly as the disease progresses, and at a certain point, the brain networks actually become hyperexcitable, despite the loss of synapses and brain cells in this brain region. Further study may point to early treatment that might prevent these electrical brain spells, as well as slow down the progression of this debilitating disease."
"Such abnormal network activity in Alzheimer's patients was thought to be a collateral or secondary event caused by the degeneration of nerve cells," said Jorge Palop, Ph.D., the study's lead author and a Gladstone research scientist. "But our study suggests that this activity may actually be a primary effect of amyloid beta and an early determinant of cognitive failure."
Amyloid beta is a toxic protein fragment found in the brains of people with Alzheimer's and similar disorders.
"Our results have important therapeutic implications, because the prevention and reversal of non-convulsive seizure activity has not yet been a major focus of clinical trials in Alzheimer's disease. Our results suggest that the suppression of this activity might prevent and possibly even reverse cognitive impairments induced by high levels of amyloid beta," said Lennart Mucke, M.D., co-senior author, professor of neurology at the University of California San Francisco and director of the Gladstone Institute.
The mice were genetically engineered by Palop, Mucke and their team. Others who took part in the research include Jeannie Chin, Erik Roberson, Jun Wang, Myo Thwin, Nga Bien-Ly, Jong Yoo, Kaitlyn Ho, Gui-Qiu Yu, Anatol Kreitzer and Steven Finkbeiner, all of Gladstone.
Funding for this work came from the National Institutes of Health and the McBean Foundation.
An abstract of this article can be found at www.neuron.org.
Original source: www.bcm.edu/archives/fromthelab/vol06/is8/1007-1.html