Alzheimer's Disease Research - Current Award

	Malcolm Leissring, Ph.D. Mayo Clinic Jacksonville Jacksonville, FL Title: Catabolism Of Amyloid Beta And Tau By Cathepsin D In Vivo Non-Technical Title: Can Alzheimer Disease Be Treated With The Enzyme Cathepsin D? Duration: April 1, 2009 - March 31, 2012 Award Type: Standard Award Amount: $400,000
Summary: We have discovered that deletion of an enzyme known as cathepsin D (CatD) in mice results in very large and very selective increases in the two toxic protein species that are most closely linked to two characteristics of Alzheimer's disease (AD): (1) the amyloid beta-protein (specifically the 42-amino acid form, amyloid beta42), which deposits in the extracellular "plaques" that characterize AD, and (2) the microtubule-associated protein, tau, which makes up the neurofibrillary tangles that form inside neurons in AD and other diseases. We hypothesize that CatD plays a protective role in preventing AD by (directly or indirectly) breaking down amyloid beta42 and tau. We will test this hypothesis by increasing or decreasing CatD levels in mice that accumulate either amyloid beta 42 or tau.

Details:

The brains of patients with Alzheimer's disease (AD) are characterized by abnormal accumulations of "plaques," which are extracellular deposits composed primarily of a protein fragment known as amyloid beta 42 and "tangles," which are fibrils that form inside neurons that are composed principally of a different protein known as tau. We have discovered that both of these proteins are destroyed by a specific enzyme known as cathepsin D (CatD), a finding that suggests it would play a protective role in preventing AD. Surprisingly, however, many years of research on the role of CatD in AD suggest that it might instead contribute to the disease. To discriminate between these two possibilities, we will increase or decrease CatD levels in mice that accumulate either amyloid beta42 or tau, then determine what the results are. If CatD is protective, as we hypothesize, then it might be possible to treat AD by increasing CatD levels with novel drugs, or by introducing the enzyme into patients directly.

Progress Updates:

Cathepsin D (CatD) is an enzyme protein implicated in the degradation of the amyloid beta-protein (Aβ) that has been repeatedly linked to the pathogenesis of Alzheimer’s disease (AD). Accordingly, we hypothesize that CatD plays a protective role in AD, an idea that runs counter to most published studies, which instead tend to suggest a pathogenic role for CatD. To test this hypothesis, we will determine the consequences of altering CatD expression in mouse models of amyloidogenesis and tau pathology. Since the complete absence of CatD in mice causes premature death (from peripheral causes), we will selectively overexpress or reduce CatD activity in mouse models of AD. To accomplish this, we will either overexpress mutant forms of human amyloid precursor protein (APP) or human tau protein. The resulting mice will be analyzed by a battery of biochemical and histopathological endpoints appropriate to each animal model.

During the first reporting period of this award, which covers ~10 months of activity, we accomplished four major goals. First, we delivered a gene-changing treatment that increased the activity of CatD in non-AD mice and quantified the degree of that increase in terms of overall levels and activity of CatD, and whether this results in premature death. Second, we attempted the same genetic increase in CatD expression/activity in our first mouse model of AD (the results of which will be available within a few months). Third, we created a new genetic-changing treatment that is intended to reduce activity of CatD and characterized its effects in cultured cells. Fourth, we prepared and bred a second mouse model of AD mice that will be required to complete this project. Finally—in very significant advances that are exceptionally important to this project, but not explicitly part of the specific aims—we made significant progress characterizing mice that lack CatD (a third model), determining the underlying mechanism that affects beta-amyloid. We also analyzed mutations in human cathepsin D. Data from both of these experiments in the fourth goal suggest that CatD is significantly associated with a risk for late-onset AD.