Recently, we have obtained direct evidence linking senile plaques and neurofibrillary tangles, the two hallmark lesions in Alzheimer's disease (AD). We cultured hippocampal neurons obtained from wild type, tau knockout, and human tau transgenic mice, and treated them with fibrillar AB. Morphological analysis indicated that neurons expressing either mouse or human tau proteins degenerated in the presence of AB. On the other hand, tau-depleted neurons showed no signs of degeneration in the presence of AB. These results suggest that tau is essential to AB-induced neurodegeneration. However, the mechanism by which tau mediates Aa toxic effects in central neurons are largely unknown. Most of the research effort in the field has been focused on the role of tau phosphorylation in neurite degeneration. We propose an alternative mechanism by which tau could mediate AB-induced neurite degeneration. We hypothesize that the deposition of fibrillar AB results in the cleavage of tau proteins. Truncated tau may contribute to neuronal cell death associated with neurodegeneration in central neurons. To test this hypothesis we propose to: 1) determine whether AB deposition induces cleavage of tau proteins; 2) identify the proteases responsible for tau cleavage in the presence of fibrillar AB; 3) determine to what extent tau cleaved fragments mediate AB neurotoxicity; and 4) determine whether factors capable of preventing Aa-induced tau cleavage prevent neuronal degeneration followed by cell death. The proposed experiments will be carried out using mature primary cultures of hippocampal neurons and AD animal models. A combination of techniques including Western blot analysis, in vitro protease assays, site-directed mutagenesis, and the suppression of protein expression by means of antisense oligonucleotides or siRNA will be used.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039080-07
Application #
7220620
Study Section
Special Emphasis Panel (ZRG1-CDIN (01))
Program Officer
Sutherland, Margaret L
Project Start
2000-03-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
7
Fiscal Year
2007
Total Cost
$250,663
Indirect Cost
Name
Northwestern University at Chicago
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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

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