We have previously shown that beta-amyloid (Aβ) oligomers induced dynamin 1 and tau cleavage in cultured hippocampal neurons. As a result of this cleavage, dynamin 1 levels decreased and a toxic tau fragment was generated. Aβ-induced cleavage of these proteins was calpain-mediated and impacted both synaptic vesicle recycling and the integrity of neuronal processes (Kelly et al., 2005;Park and Ferreira, 2005;Ferreira, 2006, Kelly andFerreira ,2007). Building on previous reports, these results identified calpain as a potential target for therapeutic intervention in Alzheimer's disease. In the present study, we tested the ability of A-705253, a novel water-soluble calpain inhibitor with oral availability and enhanced metabolic stability, to prevent Aβ-induced dynamin 1 and tau cleavage in cultured hippocampal neurons. Quantitative Western blot analysis indicated that the incubation of these cells with A-705253 prior to the addition of oligomeric Aβ reduced both dynamin 1 and tau cleavage in a dose-dependent manner. In addition, our results showed that this calpain inhibitor significantly ameliorated the cleavage of these proteins when added simultaneously with oligomeric Aβ. Furthermore, our data indicated that the use of this calpain inhibitor could have some beneficial effects even when added after the cleavage of these proteins have been triggered by Aβ. Collectively, these results suggest that, indeed, specific calpain inhibitors could play an important role in the treatment of Alzheimer's disease.
KeywordsAlzheimer's disease; proteolysis; tau; dynamin 1; calpain inhibitors Two types of pathological structures, senile plaques and dystrophic neurites containing neurofibrillary tangles, are easily detectable in brain areas associated with learning and memory *Correspondence should be addressed to: Adriana Ferreira, M.D., Ph.D., Department of Cell and Molecular Biology, Ward Building Room 8-140, 303 East Chicago Avenue, Chicago, IL 60611, Phone (312) 503 0597, Fax (312) 503 7345, E-mail: aferreira@northwestern.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (Glenner and Wong, 1984;Kosik et al., 1986;Wood et al., 1986;Kondo et al., 1988;Yankner and Mesulam, 1991;Selkoe, 1994;Parihar and Hemnani, 2004;Stern et al., 2004). The coexistence of senile plaques and neurofibrillary tangles in the same brain areas prompted the search for a potential mechanistic link between them. Most of those studies, carried out using cultured neurons as model systems, supported the hypothesis that aggregated Aβ triggered tau phosphorylation followed by the formation of dystrophic neu...
