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2008 Grants - Mobley
Degeneration of Hippocampal Circuits in Down Syndrome: a Role for APP?
William Mobley, M.D., Ph.D.
The Regents of the University of California, San Diego
San Diego, California
2008 Investigator-Initiated Research Grant
Every person has 23 pairs of chromosomes. An individual with Down syndrome, however, has an extra copy of chromosome 21. Many people with Down syndrome develop the pathological features and symptoms of Alzheimer's disease in middle age.
Alzheimer's disease and Down syndrome share many underlying characteristics. Both involve loss of function in the hippocampus, a brain region important for learning and memory. Both disorders also involve damage to brain cells that promote hippocampal health. These cells include basal forebrain cholinergic neurons (BFCNs), which have long, thin structures called axons that help transmit chemical messages into the hippocampus. Damage to BFCN axons may lead to memory loss and cognitive decline.
In preliminary studies, William Mobley, M.D., Ph.D., and colleagues analyzed mice genetically engineered to develop symptoms of Down syndrome, Alzheimer's disease or both disorders. They found that the disorders strongly affected BFCN axons. Specifically, the researchers noticed that certain axons lost the ability to transport nerve growth factor, a protein that promotes nerve cell growth and protects cells from damage. Further research found that this axonal abnormality was associated with increased levels of amyloid precursor protein (APP). APP is the parent molecule of beta-amyloid, a key suspect in Alzheimer's.
For this grant, Dr. Mobley and colleagues will use their mice to conduct a more extensive study of the role of hippocampal cells in Alzheimer development. The researchers hope to confirm their earlier results with BFCNs. But they will also look for other cell groups that experience Alzheimer-related axonal damage. In addition, they hope to confirm that abnormal APP regulation is linked to this damage and to the subsequent loss of function in the hippocampus.
Results of Dr. Mobley's study could lead to new therapies for both Alzheimer's disease and Down syndrome.