NIBN Director
Ph.D.: Weizmann Institute of Science, Israel
Post-doctorate: University of Wisconsin-Madison, USA and
University of Toronto, Canada
Position: Professor, NIBN Director
Department of Life Sciences
Faculty of Natural Sciences
E-mail: vardasb@bgu.ac.il
VDAC1 as a potential target for Alzheimer's disease therapy
Alzheimer’s disease (AD) is the most common form of dementia in the elderly. AD is characterized by cognitive decline and the occurrence of brain senile plaques and neurofibrillary tangles, as well as associated with the loss of brain synapses and synaptic dysfunction. In consort with these pathologies, increasing evidence also points to structural and functional abnormalities of mitochondria. Clinical findings strongly suggest that early aggregation of the amyloid beta peptide (Aβ) plays a key role in AD pathogenesis. Moreover, Ab deposits were found both in extracellular and intra-neuronal in the brains of AD patients early in the disease process. Moreover, it has been shown that synaptic damage and mitochondrial dysfunction are early events in AD pathogenesis, with Ab-induced cytotoxicity having been shown to be preceded by mitochondrial dysfunction and signaling events characteristic of apoptosis in cultured cells. While mitochondrial dysfunction occurs early in AD and is a prominent feature of the disease, the underlying mechanisms remain poorly understood. However, it has been recently shown that the voltage-dependent anion channel (VDAC), located in the outer mitochondrial membrane participates in Ab-induced toxicity. This finding underscores a definitive causative link between awry mitochondrial function and the development of AD.
VDAC1 functions in both cell metabolism and apoptosis can be modified by Ab interaction with VDAC1, leading to mitochondrial dysfunction and apoptosis. Using biophysical and biochemical methods, we have demonstrated that Aβ directly interacts with VDAC1 and with a peptide corresponding to VDAC1’s N-terminal domain. This peptide completely prevents Aβ entry into PC-12 and SHSY-5Y cells and resultant cytotoxicity. In addition, silencing VDAC1 expression by a specific siRNA prevented Aβ association with the cell membrane and intracellular accumulation. Therefore, we hypothesize that Aβ toxicity involves mitochondrial impairment mediated via Aβ interaction with both mitochondrial and plasmalemmal (pl)VDAC1. As a VDAC1 N-terminal-based peptide protects against Ab-related cytotoxicity and its cell penetration, we hypothesize that Ab cytotoxicity is mediated via its interaction with the VDAC1-N-terminal domain and that Ab penetrates the cell via pl-VDAC1 that we predict is over-expressed in AD brains. However, the exact mechanism by which VDAC1 mediates Ab cytotoxicity and the sequence of events leading to such toxicity have yet to be explored.
Our overall goal is to scrutinize the relationship between Aβ interaction with VDAC1 and apoptosis induction and translate these findings into the development of VDAC1-based peptide therapeutics as effective anti-Ab treatment for AD.
Elucidating the role of the VDAC1-Ab interaction and the involvement of pl-VDAC1 in Ab cytotoxicity will provide new insights into the mechanisms that control Ab cytotoxicity in AD pathogenesis and contribute to the development of VDAC1-based pharmacological interventions.
Shoshan-Barmatz V., Israelson A., Bridiczka D. and Sheu S.S. (2006). The Voltage Dependent Anion Channel (VDAC): Function in Intracellular Signalling, Cell Life and Cell Death. Current Pharmaceutical design 12(18):2249-2270.
Shoshan-Barmatz V., de Pinto V., Zweckstetter M., Raviv Z., Keinan N. and Arbel N. (2010). VDAC, a multi-functional mitochondrial protein regulating both cell life and death. Molecular Aspects of Medicine 31:227-286.
Varda Shoshan-Barmatz (2014). Amyloid-Beta binding peptides and use thereof for treating neurodegenerative diseases. U.S. Provisional Patent Application No. 61/935,363
