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2014 Grants - Marcello
Development of Innovative Tools for Alzheimer's Disease Therapy
Elena Marcello, Ph.D.
University of Milan
2014 New Investigator Research Grant
The protein fragment beta-amyloid is a key suspect in Alzheimer's disease. This fragment is “clipped” from its parent molecule, amyloid precursor protein (APP), and tends to accumulate into clumps called amyloid plaques — a hallmark of Alzheimer’s disease. Scientists do not understand exactly how beta-amyloid clumping occurs. However, current research has found that a protein called ADAM10 (A disintegrin and metalloproteinase 10) may be involved. This protein normally exists on the outer surface of cells, where it helps prevent the clipping of beta-amyloid from APP. But the improper transportation of ADAM10 (away from the outer surface) may prevent it from carrying out its regular function, thus promoting disease-related amyloid production. For people with Alzheimer’s disease, abnormal alterations in a process called endocytosis, in which proteins on the cell’s outer surface are internalized in the cell, may lead to improper transport of ADAM10.
In preliminary studies, Elena Marcello, Ph.D., and colleagues looked for a mechanism that might explain why ADAM10 may be affected by endocytosis. They found that for people with Alzheimer’s disease, ADAM10 binds abnormally to an endocytosis-related protein called AP2. This binding may promote the removal of ADAM10 from the cell’s surface, leading to accumulation of beta-amyloid. The team also found that in mice engineered to develop Alzheimer’s-like brain changes, abnormal binding of ADAM10 to AP2 occurs well before the development of observable brain changes (e.g. beta-amyloid accumulation) and memory problems.
For their current grant, Dr. Marcello and colleagues have designed proteins called cell permeable peptides (CPPs), which can interfere with ADAM10 binding to AP2. They will administer the CPPs into their Alzheimer’s-like mice and determine whether they can prevent ADAM10 from becoming internalized and dysfunctional — and whether the rescue of ADAM10 activity can prevent memory decline and beta-amyloid clumping in the mouse brains. Results of this effort could shed new light on how Alzheimer’s disease begins and may provide potential targets for new drug therapies.