Giuseppina Tesco, MD, PhD Giuseppina Tesco, MD, PhD

Assistant Professor

Giuseppina Tesco is an Assistant Professor and member of the Genetics and Aging Research Unit at MIND. She studies the molecular processes that occur in brain cells during the development of Alzheimer's disease, specifically the production of amyloid-beta, the key component of senile plaques seen in the brains of patients with Alzheimer's disease.

Amyloid-beta is formed when the larger amyloid precursor protein (APP) is clipped by two enzymes - beta-secretase, also known as BACE, and gamma-secretase. These enzymes release the toxic amyloid-beta fragment that forms plaques, so Dr. Tesco has been studying the regulation mechanisms of both beta-secretase and gamma-secretase.

It has been known for several years that strokes and head injuries can increase the risk of Alzheimer's disease, but the mechanism underlying that increased risk has not been understood. Dr. Tesco’s group has shown how brain cell death caused by these traumas can lead to the production of amyloid-beta through the dysregulation of BACE levels in the brain. She identified a novel mechanism of regulation of BACE levels and activity by the trafficking molecule GGA3 (golgi-localized gamma-ear-containing ARF binding protein 3).

Damaged brain cells undergo cell death or apoptosis, activating caspases which also break down the GGA3 molecule. Dr. Tesco found that GGA3 is necessary for the degradation of BACE, probably by targeting BACE to lysosomes. During apoptosis in vitro, GGA3 is cleaved by caspases, allowing BACE levels to rise. In a rat model of stroke, Dr. Tesco reported GGA3 cleavage products and BACE accumulation, which shows that caspase activity regulates this pathway after injury. The importance of GGA3's control of BACE levels was supported by the observation that, in brain tissue from Alzheimer's patients, reductions in GGA3 corresponded with elevations in BACE, particularly in those areas most affected by the disease.

Amyloid-beta itself is toxic to brain cells, so it may cause further apoptosis, leading to a vicious cycle of continued cell death and amyloid-beta production.

This work shows that stroke, and perhaps head trauma, can trigger a series of biochemical events that increase amyloid-beta production in the brain, and subsequent development of Alzheimer’s disease. Novel therapies could interfere with this process and reduce the risk of Alzheimer's disease in stroke or head trauma patients.

Selected Publication

Tesco G, Koh YH, Kang EL, Cameron AN, Das S, Sena-Esteves M, Hiltunen M, Yang SH, Zhong Z, Shen Y, Simpkins JW, Tanzi RE. Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity. Neuron 54, 721-737.