Summary
A key missing link in the pathogenesis of Alzheimer’s disease is the connection between the complex processing of the amyloid precursor protein (APP) to form senile plaques and the polymerization of the tau protein into the paired helical filaments of neurofibrillary tangles. While both plaques and tangles are required for the clinical expression of Alzheimer’s disease, understanding how the two component proteins of these structures are related is problematic. One possibility being explored by some investigators is that the Aβ fragment is directly toxic to neurons, and aggregates of this fragment can induce both a cytoskeletal reorganization and ultimately cell death. While these experiments are compelling when performed in culture, the presence of amyloid fibrils in the post-mortem brain often seems relatively benign. Brain tissue in the region of amyloid deposition, particularly diffuse amyloid, can be unremarkable, and neurofibrillary tangles often occur at sites anatomically distant from plaques.
We have found that a secreted fragment of APP can stimulate the mitogen-activated protein kinase (MAPK) in a ras-dependent manner and that stimulation along this pathway results in the enhanced phosphorylation of tau protein. Phosphorylation at several recently identified sites is one means by which tau function is mediated. Our recent observations suggest that tau effects its function not just by interacting with microtubules, but also with other elements of the cytoskeleton. One of these interactions that appears important in the initiation of processes is a direct or indirect interaction between tau and the actin system. In Sf9 cells expressing tau, the segregation of actin filments to one pole of the cell anticipates process formation. The induction of this type of organization suggests a role for tau in establishing polarity.
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Kosik, K.S., Ferreira, A., Knowles, R., Leclerc, N., Greenberg, S.M. (1995). Linking Amyloid Precursor Protein Processing and Tau-Related Pathology in Alzheimer’s Disease. In: Kosik, K.S., Selkoe, D.J., Christen, Y. (eds) Alzheimer’s Disease: Lessons from Cell Biology. Research and Perspectives in Alzheimer’s Disease. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-79423-0_19
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DOI: https://doi.org/10.1007/978-3-642-79423-0_19
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