People / Tesco Laboratory

Alzheimer’s Disease Research Laboratory

Giuseppina Tesco, M.D., Ph.D.
Assistant Professor of Neuroscience
Phone: (617) 636-4050
Fax: (617) 636-2413
Giuseppina.Tesco@Tufts.edu

Search for recent publications by Giuseppina Tesco

Research Interests

Alzheimer's disease (AD) is a devastating neurodegenerative disorder that results in loss of memory and cognitive function, eventually leading to dementia. A key neuropathological event in AD is the cerebral accumulation of an ~4kDa peptide termed Aβ, the principle component of senile plaques. Amyloid plaques are formed by aggregates of amyloid-β-peptides, 37-43 amino-acid fragments (predominantly Aβ₄₀ and Aβ₄₂) derived by serial proteolysis of the amyloid precursor protein (APP) by Beta-site APP-cleaving enzyme (BACE1) and γ-secretase. Aging, genetic factors and head trauma are major risk factors for AD. Additionally, stroke significantly increases the risk of AD, operating as either a precipitating or “triggering” event. AD is a complex disease influenced by the actions of multiple genes, their interactions with each other and with the environment. In a small percentage (>1%) of cases AD is inherited as an autosomal dominant trait (Familial AD), however the majority of cases are sporadic. To date, the only strong genetic risk factor for sporadic AD is represented by the inheritance of APOe4 allele. Several studies have shown that BACE1 protein levels and β-secretase activity are increased in AD brains. To date, several transcriptional and post-transcriptional mechanisms have been reported to regulate BACE1 levels. The regulation of BACE1 levels seems to be mediated by molecular mechanisms influenced by both genetic and environmental factors. Thus, BACE1 elevation may be the first step in increasing Aβ and triggering AD pathology, at least in the sporadic cases.

Our studies have elucidated a novel mechanism of regulation of BACE1 mediated by the BACE1-interacting molecule, GGA3. GGA3 is involved in trafficking ubiquitinated cargo to lysosomes for degradation. We have determined that RNAi-mediated depletion of GGA3 increases levels and activity of BACE1 in vitro. Moreover, caspase-mediated depletion of GGA3 results in stabilization of BACE1 and enhanced β-secretase activity during apoptosis both in vitro and in murine models of cerebral ischemia and traumatic brain injury. Levels of GGA3 are decreased in post-mortem AD brain and inversely correlated with BACE1 levels suggesting that subjects with low levels of GGA3 may be at risk of developing AD with aging and/or in association with acute brain injuries.

We are currently studying the effect of GGA3 genetic deletion on BACE1 levels and activity, behavior and synaptic transmission.

Lab Members

Kendall R. Walker, PhD
Eugene L. Kang, BA, MPH
Andrew N. Cameron, BA

Post-Doc positions available

Selected Publications

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.