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Unraveling the Accumulation of Amyloid-Beta in Alzheimer’s Disease

Giuseppina Tesco Giuseppina Tesco, MD, PhD, joined the Department of Neuroscience in 2009. Tesco is working on mechanisms of regulating amyloid-beta peptide, which accumulates in the brains of people affected by Alzheimer’s disease. Amyloid-beta accumulation likely contributes to the clinical manifestations of the disease, which include progressive memory loss, cognitive impairment, confusion, and personality changes. Tesco’s research focuses on beta-site APP-cleaving enzyme (BACE) 1, also known as beta-secretase, which is a limiting step in the production of amyloid-beta. “BACE1 elevation may be the first step in increasing amyloid-beta and triggering Alzheimer’s disease pathology, at least in the sporadic cases,” says Tesco.

Offering collaboration in

  • Alzheimer’s disease
  • traumatic brain injury

Seeking collaboration in

  • protein trafficking and degradation
  • the ubiquitin pathway

Tesco earned her MD and PhD (in neuroscience) from the University of Florence. She did research at the Laboratory of Adaptive Systems (Daniel Alkon, chief), National Institute of Neurological Disorders and Stroke, as both a Fogarty postdoctoral visiting fellow and a visiting associate. She also worked as a visiting associate at the Genetics and Aging Research Unit, Massachusetts General Hospital, Department of Neurology, Harvard Medical School. Tesco was a faculty member at Harvard (neurology) before joining Tufts.

Over 99% of Alzheimer’s disease cases are sporadic and not inherited. “So basically, in these cases, many factors can contribute to the accumulation of amyloid-beta in the brain,” says Tesco. “Several groups have found that BACE1 increases in the brains of Alzheimer’s disease patients. If BACE1 increases, amyloid-beta increases.” Hence, decreasing or inhibiting cerebral BACE1 may lead to decreasing amyloid-beta and Alzheimer’s symptoms. However, efforts to develop inhibitors of BACE1 that are effective in the central nervous system have had limited success.

Tesco’s research group is working on three approaches to decreasing BACE1 activity. The first builds on the knowledge that BACE1 needs to be in the acidic environment of the endosome in order to be most active. “If you can prevent BACE1 from reaching the acidic compartment, maybe you can reduce the activity,” says Tesco.

Another approach involves increasing BACE1 degradation. Working in an animal model of stroke, Tesco’s group found a molecular mechanism that is responsible for transport of BACE1 to the lysosome, where it is degraded. The BACE1 transport molecule is called Golgi-localized, gamma adaptin ear–containing, ARF-binding protein 3, or GGA3. “Decreased levels of GGA3 result in BACE1 accumulation,” says Tesco. “GGA3 is depleted following both stroke and traumatic brain injury in mice. We took advantage of a novel mouse model in which the GGA3 gene is deleted (a GGA3 knockout mouse), and we found that caspase-mediated depletion of GGA3 is responsible for 50% of BACE1 elevation following injury. We also found that having only 50% of GGA3 (mice that carry one copy of the GGA3 gene) produces a persistent elevation of BACE1 and amyloid-beta over time following head trauma. This is a very exciting finding because it looks like people who might have decreased levels of GGA3 in their brains for several reasons, even genetic reasons, could be at risk of developing Alzheimer’s disease.” Strokes and traumatic brain injuries may increase the risk of Alzheimer’s disease by causing brain cell death, a decrease in GGA3, an increase in BACE1, and therefore an increase in amyloid-beta.

The third approach also involves increasing BACE1 degradation. It is based on the finding that BACE1 needs to be modified by the ubiquitin pathway for GGA3 to bind and transport BACE1 to the lysosome. Tesco’s research group is working on ways to increase BACE1 ubiquitination in order to increase its degradation in the lysosome.

To summarize, the hope is to decrease cerebral accumulation of amyloid-beta by (1) limiting BACE1 uptake by the endosome to decrease BACE1 activity, (2) increasing GGA3 expression to increase BACE1 transport to the lysosome for degradation, and (3) increasing BACE1 ubiquitination to increase BACE1 transport to the lysosome. These three mechanisms of BACE1 regulation represent potential therapeutic targets for the treatment of Alzheimer’s disease.

For collaboration, Tesco offers her expertise in Alzheimer’s disease and mouse models of traumatic brain injury. She is interested in finding collaborators in the fields of protein trafficking and degradation, and the ubiquitin pathway.

For more information, please go to http://sackler.tufts.edu/Academics/Degree-Programs/PhD-Programs/Faculty-Research-Pages/Giuseppina-Tesco.aspx.

 

 

 

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