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Dissertation/Thesis Abstract

Spreading the seeds of neurodegeneration: Tau fibrils enter cells by macroendocytosis
by Jacks, Rachel Lauren, Ph.D., University of California, San Francisco, 2010, 63; 3412279
Abstract (Summary)

The deposition of tau protein characterizes over 20 neurodegenerative disorders, among them Alzheimer’s disease and fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Neurodegeneration and dementia have been shown to be caused by mutations in the tau gene [1-3]. The presence of tau is necessary for β-amyloid-induced neurotoxicity in cultured neurons and extracellular tau aggregates are taken up by cells and can induce the misfolding of intracellular tau [4, 5]. In order to determine the mechanism of cellular entry, we used the mouse undifferentiated neuronal precursor C17.2 line to study the uptake of recombinant extracellular tau fibrils using fluorescence and EM imaging. We found that tau fibrils are internalized in a saturable, actin-, energy- and temperature-dependent manner that does not require clathrin. This internalization can be blocked by the macropinocytosis inhibitors rottlerin and amiloride. Degradation of internalized tau can be blocked by the lysosomal inhibitors bafilomycin A and ammonium chloride. EM imaging indicates that fibrils are engulfed by the membrane in a manner consistent with a macroendocytic process, and are then contained within membrane-bound structures. This provides a mechanism to understand how extracellular tau aggregates can gain entry to cells, and could potentially lead to the development of drugs to block this internalization.

Indexing (document details)
Advisor: Diamond, Marc I.
Commitee: Brodsky, Frances, Edwards, Robert
School: University of California, San Francisco
Department: Biomedical Sciences
School Location: United States -- California
Source: DAI-B 71/08, Dissertation Abstracts International
Subjects: Molecular biology, Cellular biology, Neurosciences
Keywords: Alzheimer's disease, Amyloids, Endocytosis, Macroendocytosis, Tau fibrils
Publication Number: 3412279
ISBN: 978-1-124-10116-3
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