We intend to establish the relationship between senile plaques and neurofibrillary tangles, the two hallmark lesions in Alzheimer's Disease. Recently, we have obtained data suggesting a link between these two lesions in hippocampal neurons. Our work builds on those models in which fibrillar beta-amyloid (Abeta) added to neurons in culture results in neurotoxicity. The addition of Abeta to mature hippocampal cultures resulted in severe alterations of neuronal morphology, including the progressive degeneration of axons and dendrites, and the selective hyperphosphorylation of adult tau isoforms. Therefore, the specific aims of this proposal are directed to obtain further and novel insights into the mechanistic link between Abeta deposition, tau hyperphosphorylation and neurite degeneration.
The specific aims will address the following hypotheses: 1) the deposition of Abeta results in the integrin-mediated activation of the mitogen-activated protein kinase (MAPK) signal transduction pathway in mature central neurons; and 2) this activation of MAPK contributes to the enhanced phosphorylation of adult tau isoforms which in term, plays a key role in the mechanism underlying neurite degeneration. We shall determine: 1) whether the activation of MAPK by fibrillar Abeta is mediated by integrins. We will attempt to block the activation of MAPK induced by Abeta by pretreating the cells with antibodies known to inhibit the function of different integrins. We will repeat these experiments using hippocampal neurons depleted of different integrins by means of homologous recombination techniques or antisense oligonucleotides. 2) The participation of MAPK in the selective phosphorylation of adult human tau isoforms induced by Abeta. The experiments will be using mature hippocampal cultures prepared from wild type, tau knockout and human tau transgenic mice treated with soluble or fibrillar Abeta. The activity of MAPK will be suppressed by means specific inhibitors. Tau phosphorylation will be determined using tau antibodies and by phosphorylation assays. The presence of signs of neurite degeneration will be assessed at the light and electron microscopy levels.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BDCN-3 (01))
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Chiu, Arlene Y
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Northwestern University at Chicago
Anatomy/Cell Biology
Schools of Medicine
United States
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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
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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
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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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