Regulation of amyloid-beta protein levels by proteolytic degradation and its implications for Alzheimer's disease
By: by Matthew Louis Hemming
Series: Collections of the Harvard University Archives
Published: 2007
Language: eng
Number of pages: 279
Description: Accumulation and deposition of the amyloid beta-protein (Aβ) is an invariant feature of Alzheimer's disease (AD). Biochemical, cell biological, animal modeling, genetic, and emerging clinical data all suggest that Aβ is an upstream initiator of the disease process and its neuropathology. Decreasing brain Aβ is an emerging therapeutic approach for AD, and currently efforts are being made to block Aβ production or enhance its clearance through vaccination. A less well understood mechanism of Aβ clearance is enzymatic degradation by proteases within the brain. The purpose of this thesis is to describe pathways of Aβ catabolism that may shed light on disease pathogenesis. Further, such insight may prove useful for assessing disease risk as well as offering preventative and therapeutic measures against the disease. I first present evidence that an enzyme genetically associated with AD, the angiotensin-converting enzyme (ACE), is an Aβ-degrading protease. I determine that ACE is expressed within the brain, and that cellular overexpression of ACE promotes the degradation of Aβ.

Using sight-directed mutagenesis, I found that both of the active sites within ACE are capable of degrading Aβ, and that ACE-mediated Aβ degradation is inhibited by a widely prescribed ACE inhibitor. To pursue the question of whether ACE inhibitors elevate Aβ levels in vivo, I chronically treated amyloid precursor protein (APP) transgenic mice with an ACE inhibitor. Though these drugs prevent ACE-mediated Aβ degradation in culture, no such effect was seen in vivo, likely due to poor brain penetration of the drug. In further studies, I generate a secreted form of the Aβ-degrading protease neprilysin that potently lowers Aβ levels in culture. I then introduce this protease by ex vivo gene delivery of primary fibroblasts into the brains of APP transgenic mice. This treatment resulted in significant clearance of both fibrillar and non-fibrillar Aβ plaques at the site of cell engraftment as well as distal to the graft. These studies shed light on how Aβ degradation plays a role in Aβ accumulation, and may offer pathways towards the prevention and treatment of Alzheimer's disease.
Notes: "September 2007."

Thesis (Ph.D., Division of Medical Sciences (Neurobiology))--Harvard University, 2007.

Includes bibliographical references.