The experiments performed during the first funded period of this project (2000-2004) led to the first evidence of a direct link between senile plaques and tau pathology in an Alzheimer's disease (AD) cell model system (Rapoport et al., 2002). This study showed that neurons expressing human tau degenerated in the presence of preaggregated beta amyloid (A?), while no signs of degeneration were detected in A?-treated tau-depleted neurons (Rapoport et al., 2002). Data obtained during the second funded period (2005-2009) have identified calpain-mediated tau cleavage leading to the generation of a 17 kDa fragment as an important step in neuronal degeneration (Park and Ferreira 2005, Park et al., 2007). More recently, we have obtained preliminary evidence suggesting that the levels of this tau neurotoxic fragment might be elevated not only in AD but also in other tauopathies. However, the mechanisms by which this tau fragment could induce neurotoxicity remain poorly understood. We speculate that the generation of a 17 kDa tau fragment is a conserved mechanism leading to neuronal degeneration in different tauopathies. To test this hypothesis, we will determine: 1) the presence of the 17 kDa tau fragment in brain samples obtained from AD and other tauopathies patients;and 2) we will generate a transgenic animal model in which this toxic fragment is over expressed. This animal model could provide an essential tool for future studies on the neurotoxic effects of this fragment in central neurons that develop in situ. These experiments will be performed by means of a combination of techniques including: Western blot analysis, immunocytochemistry, calpain activity assays, real-time RT-PCR, and homologous recombination techniques. The data obtained could provide useful for the diagnosis, prevention, and eventually the treatment of AD and other tauopathies.

Public Health Relevance

The goal of this project is to study a novel and poorly understood mechanism underlying neuronal degeneration. This mechanism involved the cleavage of the microtubule-associated protein tau by calpain. Obtaining this information could provide useful for the diagnosis, prevention, and eventually the treatment of Alzheimer's disease and other tauopathies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Corriveau, Roderick A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Northwestern University at Chicago
Anatomy/Cell Biology
Schools of Medicine
United States
Zip Code
Lang, A E; Riherd Methner, D N; Ferreira, A (2014) Neuronal degeneration, synaptic defects, and behavioral abnormalities in tau?????? transgenic mice. Neuroscience 275:322-39
Nicholson, Alexandra M; Methner, D Nicole Riherd; Ferreira, Adriana (2011) Membrane cholesterol modulates {beta}-amyloid-dependent tau cleavage by inducing changes in the membrane content and localization of N-methyl-D-aspartic acid receptors. J Biol Chem 286:976-86
Ferreira, Adriana; Sinjoanu, Roxana C; Nicholson, Alexandra et al. (2011) A* toxicity in primary cultured neurons. Methods Mol Biol 670:141-53
Nicholson, Alexandra M; Ferreira, Adriana (2010) CHOLESTEROL AND NEURONAL SUSCEPTIBILITY TO BETA-AMYLOID TOXICITY. Cogn Sci (Hauppauge) 5:35-56
Nicholson, Alexandra M; Ferreira, Adriana (2009) Increased membrane cholesterol might render mature hippocampal neurons more susceptible to beta-amyloid-induced calpain activation and tau toxicity. J Neurosci 29:4640-51
Sinjoanu, Roxana C; Kleinschmidt, Sara; Bitner, Robert S et al. (2008) The novel calpain inhibitor A-705253 potently inhibits oligomeric beta-amyloid-induced dynamin 1 and tau cleavage in hippocampal neurons. Neurochem Int 53:79-88
Park, S-Y; Tournell, C; Sinjoanu, R C et al. (2007) Caspase-3- and calpain-mediated tau cleavage are differentially prevented by estrogen and testosterone in beta-amyloid-treated hippocampal neurons. Neuroscience 144:119-27
Kelly, B L; Ferreira, A (2007) Beta-amyloid disrupted synaptic vesicle endocytosis in cultured hippocampal neurons. Neuroscience 147:60-70
Kelly, Brent L; Ferreira, Adriana (2006) beta-Amyloid-induced dynamin 1 degradation is mediated by N-methyl-D-aspartate receptors in hippocampal neurons. J Biol Chem 281:28079-89
Park, So-Young; Ferreira, Adriana (2005) The generation of a 17 kDa neurotoxic fragment: an alternative mechanism by which tau mediates beta-amyloid-induced neurodegeneration. J Neurosci 25:5365-75

Showing the most recent 10 out of 17 publications