• Dickson, Dennis W (PI)
  • Lah, James (PI)
  • Counts, Scott (PI)
  • Ikonomovic, Milos D. (PI)
  • Leurgans, Sue E. (PI)
  • Beckett, Laurel (PI)
  • Trojanowski, John Q. (PI)
  • Levey, Allan (PI)
  • Binder, Lester Irvin (PI)
  • Dekosky, Steven (PI)
  • Mufson, Elliott (PI)
  • Lah, James (PI)
  • Counts, Scott (PI)
  • Ikonomovic, Milos D. (PI)
  • Leurgans, Sue E. (PI)
  • Trojanowski, John Q. (PI)
  • Ikonomovic, Milos D. (PI)
  • Beckett, Laurel (PI)
  • Trojanowski, John Q. (PI)

Project: Research project

Project Details


The brains of demented Alzheimer's disease (AD) patients are
characterized by abundant senile plaques (Sps) and neurofibrillary
tangles (NFTs). Further, the quantity of NFTs correlates with the
dementia in AD, and cerebrospinal fluid (CSF) tau levels are
abnormally high in most AD patients consistent with the fact that the
subunits of paired helical filaments (PHFs) in AD NFTs are altered
forms of tau (PHFtau). Despite the presence of small numbers of
NFTs in the brains of non-demented elderly subjects, the molecular
and cellular substrates of age-related, mild cognitive impairments in
otherwise normal elderly individuals are not known. Although PHFtau
is abnormally phosphorylated, we showed that biopsy derived normal
adult human tau is phosphorylated at nearly all of the sites previously
identified in PHFtau, albeit to a lesser extent. Further, biopsy derived
tau proteins are rapidly dephosphorylated at sites that are retained in
PHFtau. Thus, differences in the phosphorylation sites and/or state of
normal human tau versus PHFtau may reflect the differential activities
of phosphatases in the control versus AD brain. Indeed, deficient
protein phosphatase 2A (PP2A) activity has been implicated in the
formation of PHFtau, and alterations in the accessory, catalytic and
regulatory subunits of PP2A could be part of a "final common
neurodegenerative pathway" leading to the generation of PHFtau,
NFTs and the death of neurons in AD. Since similar mechanisms also
might account for milder cognitive impairments in otherwise normal
elderly individuals, we will test the hypothesis that alterations in PP2A
subunits may play a role in the pathogenesis of neurofibrillary lesions
in normal aging, and that low levels of neurofibrillary lesions may
contribute to mild cognitive impairments in the elderly. These studies
will be conducted in well characterized elderly members of a "religious
orders study cohort" with no or mild cognitive impairments versus
dementia due to AD.
Effective start/end date9/1/971/31/19


  • Medicine(all)