AGING AND ALZHEIMER DEMENTIA--ROLE OF FIBROUS PROTEIN

  • Yen, Shu-Hui C, (PI)

Project: Research project

Description

The long-term goal of this project is the understanding of the biology and
molecular pathogenesis of Alzheimer's disease (AD), the most common organic
dementia seen in old age. AD is characterized by the presence of
neurofibrillary tangles which consist primarily of paired helical filaments
(PHF). PHF preparations contain aberrant forms of tau named epitopes but
differed in reactivity with a monoclonal anti-tau antibody (Tau-1) and
antibodies to a region of bovine tau encoded by tau gene exon 2. A
pretreatment of PHF-tau with phosphatase improved its binding with these
antibodies, suggesting that PHF-tau differed from normal tau in the site/or
the extent of phosphorylation. We have shown recently that PHF-tau also
differed from normal tau in molecular mass and isoelectric charge.
Dephosphorylation had very little effect on the biochemical properties of
PHF tau, suggesting that post-translational modifications, besides
phosphorylation, and/or alternative gene splicing play a role in the
formation of PHF-tau. It remains to be determined if PHF-tau, besides the
two regions mentioned above, contain other aberrant regions, and if
phosphorylation is the only biochemical modification that distinguishes
PHF-tau from normal tau. It is also unknown if PHF-tau contains additional
phosphorylation sites and if the aberrant phosphorylation of PHF-tau is
catalyzed via a protein kinase (s) in normal brains or only in AD brains.
These questions will be answered by comparing PHF-tau, and tau proteins
from normal and AD brains for their phosphate content, amino acid
composition and sequences, post-translational modifications and by studying
the rephosphorylation of dephosphorylated PHF-tau with known kinases and
kinases from brain homogenates. A subtoxic level of glutamate or calcium
ionophore A23187 was recently shown to alter the immunoreactivity of tau in
cultured neurons. It is unclear whether this alteration is similar to that
in PHF-tau. Our last specific aim is to study the effect of these
treatments on the biochemical and immunocytochemical properties of tau, and
on the ultrastructure of the affected neurons.
StatusFinished
Effective start/end date5/1/8311/30/00

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $294,308.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $238,825.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

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Scleroproteins
Alzheimer Disease
Intermediate Filaments
Brain
Post Translational Protein Processing
Phosphorylation
Neurofibrillary Tangles
Amyloid Plaques
D-Aspartic Acid
Neurons
Phosphoric Monoester Hydrolases
Neuropil Threads
Antigens
Phosphates
Epitopes
Sodium Dodecyl Sulfate
tau Proteins
Electron Microscopy
Proteins
Neurofilament Proteins

ASJC

  • Medicine(all)