Now, on the same team, under the direction of J. Kevin Foskett, PhD, Professor of Physiology and a student, Dustin shilling, has determined that the hyperactivity of the calcium channels alleviated FAD-like symptoms in mice models of the disease to suppress. Their findings appear this week in the Journal of neuroscience.
Current therapies for Alzheimer's disease are drugs, the treatment of the symptoms of cognitive and dementia and medication, the pathology to treat Alzheimer's disease are experimental. These new observations suggest that approaches by modulating calcium signaling could be examined on the basis of, Foskett says.
The two proteins called, PS1 and PS2 (Presenilin 1 and 2), interact with a calcium release channel, the inositol-Trisphosphate receptor (IP3R), in the endoplasmic reticulum. Mutant PS1 and PS2 to increase the activity of the IP3R, in turn increased calcium in the cell. "We set out to answer the question: is increased calcium signal by the Presenilin-IP3R interaction, at the development of familial Alzheimer's disease symptoms, including dementia and cognitive deficits?" Foskett says. "" "And with views of the results of these experiments, the answer is a clear 'Yes.'"
Robust phenomenon
Excessive intracellular calcium signaling is a robust phenomenon seen in cells expressing FAD verursachender mutant Presenilins, in both human cells in culture and in mice. The team put two BLAND looking mouse models for these connections. In particular, they found that this receptor in the brain, to 50 percent signals in neurons of the cortex reduce the expression of the IP3R1, the dominant form and hippocampus in both mouse models normalized observed excessive calcium.
In addition observed with 3xTg mouse-animals FAD mutation containing Presenilin 1 with one, as well as the mutated human Tau protein and APP gene expression gebracht-- the team that the reduced expression of IP3R1 deeply amyloid plaque accumulation in brain tissue and Hyperphosphorylation of Tau protein, a decreased biochemical hallmarks of advanced Alzheimer's disease. Reduced expression of IP3R1 saved also defective electrical signalling in the memory deficits in the 3xTg mice, and hippocampus, as well as conduct tests measured.
"Our results show that excessive calcium signaling, the Presenilin mutations in familial Alzheimer's disease is, is mediated by the IP3R and contributes to the symptoms of illness in animals", Foskett says. "With this, you know now the IP3 pathway could accommodate a potential therapeutic target molecule for patients mutations in the Presenilins in connection with AD are considered."
The hypothesis of "Calcium dysregulation"
"The" calcium dysregulation "hypothesis for inherited, early onset familial Alzheimer's disease by früheren research results in the laboratory Foskett proposed. Alzheimer's disease affects more than 5 million Americans, 5 percent who have familial form. The hallmark of the disease is the accumulation of tangles and plaques of amyloid beta protein in the brain.
"The ' amyloid hypothesis", which postulates, that the primary defect is an accumulation of toxic amyloid in the brain has long used, to explain the cause of Alzheimer's disease "Foskett says. 2008 neuron study the cells that the disease-causing mutant showed in his laboratory carried out of PS1 form processing of amyloid-beta that depends on the interaction of the IP3R PS proteins, increased. This observation combines dysregulation of calcium within cells with the production of amyloid, a characteristic feature in the brains of people with Alzheimer's disease.
Clinical studies for AD have set up largely in the reducing amyloid in the brain. So far, says Foskett, these studies have non-therapeutic benefits to demonstrate. One idea is that the intervention in the disease process started too late. Accordingly, clinical trials in progress using anti-amyloid FAD asymptomatic patients now because it is known that they will eventually develop the disease while predicting who will develop the common form of AD is much less certain.
"There was an assumption that FAD simply display with an earlier, more aggressive occur, is," Foskett says. "But we do know whether the etiology of the FAD pathology is identical to that for general viewing. The relevance of the search results for the understanding of the common AD is not so clear. It is important, in my opinion is to recognize that the AD could be a range of diseases, lead together end-stage diseases. "FAD could therefore an orphan disease, and it is important to effective treatments, especially for these patient-those who are on the IP3R and calcium signal."