Working on genetically modified mice, the researchers found that using specific antibodies to clear a certain type of brain lesion reversed abnormalities arising from a second type of brain lesion, which halted the progression of the disease. Researchers also found that the earlier the treatment begins, the better the chances of success - findings that have similar implications for people, emphasizing the need for better means of early diagnosis and treatment of patients with Alzheimer's disease.
The findings are reported in the Aug. 5 issue of Neuron.
"Current estimates indicate that by the middle of the century, 20 million Americans will suffer from Alzheimer's disease," said Frank LaFerla, associate professor of neurobiology and behavior and head of the research team. "Our results have direct implications for the clinical treatment of this insidious disease."
Alzheimer's is a progressive disease and the most common cause of dementia among the elderly in the United States, affecting 4.5-5 million adults 10 times more than those affected by Parkinson's disease. The disease is marked by the accumulation of two distinct brain lesions beta-amyloid plaques and neurofibrillary tangles. Both plaques and tangles accumulate in specific brain regions critical to learning and memory.
It is believed that their accumulation contributes to the destruction of brain cells and the eventual loss of memory. The belief among many neuroscientists that the accumulation of amyloid plaques is the initiating trigger of the disease process constitutes the "amyloid cascade hypothesis" - a controversial theory in neuroscience. By showing that the progression of Alzheimer's can be stopped by early treatment of the plaques, the new findings strongly support the hypothesis.
"We found that when we cleared amyloid plaques from the brains of mice, the downstream consequences of the disease were lessened and even removed, provided the disease had not progressed to a certain advanced state," said LaFerla, who is associate director of the UCI Institute for Brain Aging and Dementia. "Our data are among the strongest experimental evidence to support the amyloid cascade hypothesis. We've demonstrated in the lab that removing plaques from the brain can indeed lead to a total clearance of tangle pathology."
LaFerla's group is now investigating if combined therapy one aimed at clearing the plaques and one specifically targeted against the neurofibrillary tangles will be effective. Such a therapy would help treat more advanced stages of Alzheimer's.
In the United States, five percent of the population over age 65 and one-third of the population over age 80 are afflicted by Alzheimer's disease. It is the third most expensive disease to treat and is the third leading cause of death, trailing cancer and coronary heart disease.
Besides LaFerla, the paper's coauthors are Salvatore Oddo, Lauren Billings, J. Patrick Kesslak and David H. Cribbs. Oddo, a third-year doctoral student in the Department of Neurobiology and Behavior, is the paper's lead author. The study, funded by grants from the National Institutes of Health and the Alzheimer's Association, is the first to evaluate a therapeutic treatment in a mouse model that more closely parallels the twin pathology that occurs in the human Alzheimer's-diseased brain.
Details of the Study:
In the study, the researchers used transgenic mice that LaFerla's lab had previously developed. Because mice normally don't get Alzheimer's, human genes were inserted into their genome, allowing the mice to develop both characteristic lesions associated with Alzheimer's disease. This uniquely positioned LaFerla's team to determine the outcome of therapies against the amyloid plaques.
The researchers administered anti-beta-amyloid antibodies into the hippocampus - one of most critical brain structures involved in learning and memory - of the mice and found that the amyloid plaques were cleared by three days, followed two days later by the clearance of the lesions caused by neurofibrillary tangles. Thirty days postinjection, when the effect of the antibodies had diminished, the researchers found amyloid plaques reemerged but the tangle lesions did not. "This suggests that these two pathologies are linked and that the development of the tangle pathology is dependent on the amyloid pathology," LaFerla said.
The researchers found, too, that there was a crucial time window when the amyloid therapy was no longer effective at removing the tangle pathology. "The tangle pathology evolves through various stages," LaFerla explained. "It turns out that the clearance of the tangles is critically dependent on their chemical state, that is, their 'phosphorylation state,' phosphorylation being the addition of phosphate groups to particular amino acids in a protein. Once the tangles become hyperphosphorylated, they are unaffected by the antibody treatment for the plaques, probably because they've become more resistant to the cellular degradation machinery. This means that the amyloid plaque-targeted therapies may be useful for clearing both hallmark neuropathological lesions of the disease, provided that the intervention is administered early in the course of the disease."
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