Structural Analysis of Human and Transgenic Mouse-derived Tau Protein Aggregates

  • Author / Creator
    Fleck, Shelaine
  • Tauopathies are a class of neurological disorders associated with the aggregation of the tau protein into neurofibrillary tangles. The most prominent tauopathy is Alzheimer’s disease (AD), which presents as two forms: early onset (familial, fAD) and late onset (sporadic, sAD). sAD does not have a known cause, although environmental, lifestyle, and genetic factors are thought to contribute to the disease manifestation. fAD can be caused by a single gene mutation in the amyloid precursor protein (APP), presenilin 1, or presenilin 2. In both forms of AD, the tau protein aggregates to form intracellular fibrillary tangles, which spread along neuronal networks. Amyloid-β, the product of APP proteolysis, also contributes to AD through the formation of extracellular amyloid plaques which, according to the amyloid cascade hypothesis, initiates all other associated pathological events, including tau deposition. Together, tau and amyloid-β lead to the extensive neuronal death seen in AD. The structure of tau fibrils in AD, either as Paired Helical Filaments (PHFs) or Straight Filaments (SFs), was solved using cryo-electron microscopy and 3D-reconstructions. By analyzing PHFs and SFs from sAD, researchers found that filament cores consist of two identical protofilaments which adopt a cross-β structure. Later, researchers analyzed additional samples from sAD and fAD cases, which confirmed the initial findings.Other tauopathies, such as frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), are caused solely by the misfolding of the tau protein. This disease is characterized by the dementia they cause and notable brain atrophy. The atomic structure of tau fibrils in FTDP-17 is currently unknown.Through imaging via electron microscopy (EM) and 3D-reconstruction of tau fibrils from both mouse and human sources, we intend to elucidate differences in tau structure which correspond with disease manifestation. There are many different diseases which the tau protein is implicated in. In this project we are focusing on Alzheimer’s disease and FTDP-17 using human and mouse brain samples, respectively.

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  • Graduation date
    Fall 2020
  • Type of Item
  • Degree
    Master of Science
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