New Clues for the Cause of Alzheimer’s Disease
A Defective ApoE Gene, Called ApoE4, Can Contribute to Causing Alzheimer's Disease by Failing to Synthesize the Synapse-Generating Enzyme, PKC Epsilon
Today, researchers at the Blanchette Rockefeller Neurosciences Institute (BRNI) at West Virginia University in Morgantown, West Virginia reported a significant advance in understanding how different forms of the ApoE gene raise the risk for Alzheimer's disease.
Among the earliest events in Alzheimer's disease is the loss of the nerve cell connections known as synapses. In a paper published in this week's issue of the Journal of Biological Chemistry, Drs. Abhik Sen, Daniel Alkon and Thomas Nelson report that the normal ApoE3 gene stimulates the growth of synapses through a protein called PKC epsilon. PKC epsilon also prevents the toxic Alzheimer's disease protein, beta amyloid, from destroying synapses. Loss of synapses in the brains of Alzheimer's disease patients is known to closely correlate with the degree of dementia.
ApoE4, a defective version of the ApoE gene, could cause the early loss of synapses in Alzheimer's disease by not stimulating the synthesis of the synaptogenic and neuroprotective protein, PKC epilson. Evidence from past studies indicates that the brains of Alzheimer's disease patients show PKC deficits.
BRNI has demonstrated over several years that PKC is essential for memory. Other BRNI studies showed that PKC protects against the loss of synapses, cognitive deficits, and toxic Alzheimer's proteins such as beta amyloid. The loss of synapses, the connections between the brain's nerve cells, causes the loss of memory and other cognitive deficits of patients with Alzheimer's disease.
What the normal ApoE does, say the researchers, is to stimulate the synthesis of PKC epsilon and its protection against synaptic loss. The researchers showed that when ApoE3, the normal gene, binds to a receptor protein called LRP1, the levels of PKC epsilon are greatly increased. When ApoE4, the abnormal gene, binds, there is no effect.
"This research breaks new ground because it shows that the normal ApoE3, but not the defective ApoE4, can control synaptogenesis and neuroprotection through PKC epsilon," said Dr. Daniel Alkon, the Scientific Director of BRNI and co-author of the paper. "This is also exciting because BRNI has developed a whole class of drugs that can reverse these effects of the defective gene as demonstrated in animal models of Alzheimer's disease as well as in synaptic networks grown in culture."
BRNI drugs that activate and increase the synthesis of PKC enhance the growth of new synapses and increase protection against the toxic beta amyloid. These drugs show the potential to prevent the loss of synapses in the early stages of Alzheimer's disease due to the abnormal ApoE4. They also show the potential to restore synapses already lost in chronic Alzheimer's disease patients.
The findings reported here and in previous studies suggest, therefore, that these drugs, known as PKC activators, could be useful in treating Alzheimer's disease. Plans to start clinical trials are now underway.
For more information on Blanchette Rockefeller Neurosciences Institute, please visit BRNI.org.