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2005 Grant - Das
Effect of Gamma-Secretase Inhibition on the Anti-Beta-Amyloid Immune Response
Pritam Das, Ph.D.
2005 New Investigator Research Grant
One of the hallmarks of Alzheimer's disease is accumulation in the brain of a small protein fragment called beta-amyloid. Research has shown that this fragment may play a primary role in Alzheimer pathology. For this reason, therapies aimed at reducing the amount of the protein are being pursued.
Pritam Das, Ph.D., and colleagues will investigate the potential benefits of combining two therapiesóa vaccine-like therapy and inhibition of a protein called gamma-secretase. Vaccination is designed to spur the body's own immune system to remove beta-amyloid. Inhibiting gamma-secretase, which is involved in production of the toxic protein fragment, is intended to prevent formation of beta-amyloid. Together the two therapies might prove more effective than either alone.
Gamma-secretase also has other roles, some of which make this combination therapy even more attractive. Recently, scientists discovered that the protein stimulates immune cells that cause inflammation. In the brain, inflammation can be particularly dangerous, and in fact, a recent clinical trial of a beta-amyloid vaccine had to be halted because of this side effect. Gamma-secretase inhibitors may, therefore, prevent unwanted inflammation.
Das and colleagues have also found that when gamma-secretase is inhibited in mice, the animals develop a stronger immune response to beta-amyloid vaccines. While the reasons for this are unclear, it suggests that the combination therapy of vaccine and gamma-secretase inhibition could yield a more robust immune defense against beta-amyloid in humans.
To further investigate the benefit of the dual therapy, Das and colleagues will use genetically altered mice that produce large amounts of beta-amyloid. The researchers will administer gamma-secretase inhibitors followed by vaccination therapy. They will monitor how rapidly beta-amyloid is cleared from the brain and investigate the reasons why the secretase inhibitor spurs the immune response. Findings could lead to new more effective treatments for Alzheimer's disease.