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2005 Grant - Han
BACE-1 Inducible Knockdown for Alzheimer's Disease Rescue
Chih J. Han, Ph.D.
Feinberg School of Medicine
2005 New Investigator Research Grant
One of the hallmarks of Alzheimer's disease is the accumulation in the brain of a protein fragment called beta-amyloid. Because this small protein is toxic to neurons and has been implicated as a major driving force behind the disease, therapies aimed at reducing the amount of the protein in the brain are being actively pursued.
One promising approach is to prevent the protein fragment from forming in the first place. In this regard, the activity of another protein called beta-amyloid precursor protein cleaving enzyme 1, or BACE1, has come in for scrutiny. BACE1 carries out the first of a two-stage process whereby beta-amyloid is clipped from a larger parent molecule. Inhibiting BACE1 could stop production and slow the accumulation of beta-amyloid.
Chih J. Han, Ph.D., and colleagues will investigate whether elimination of BACE1 could slow or prevent the progression of Alzheimer-like symptoms in mice. The researchers will use a special kind of genetically altered mouse in which the gene that carries the blueprint for human BACE1 can be switched off once the animal begins to show symptoms of the disease. The researchers will also use a slightly different approach to inhibit BACE1—the use of a chemical inhibitor to "silence" the BACE1 gene. This second approach could, at least theoretically, be used in humans.
To test if the BACE1 inhibition has any impact on the mice, the researchers will test the animals' memories before, during and after treatment. They will also measure how much beta-amyloid accumulates in the brain. If reducing the activity of BACE1 slows progression of disease in these mice, then the strategy may prove beneficial in humans with Alzheimer's disease.