• Younkin, Steven G (PI)
  • Caplan, Arnold I. (PI)
  • Whitlatch, Carol J. (PI)
  • Stuckey, Jon C. (PI)
  • Patterson, Marian (PI)
  • Fagan, Joseph (PI)
  • Ripich, Danielle (PI)
  • Friedland, Robert (PI)
  • Gilmore, Grover (PI)
  • Kalaria, Rajesh (PI)
  • Anetzberger, Georgia (PI)
  • Gambetti, Pierluigi (PI)
  • Smyth, Kathleen (PI)
  • Herrup, Karl (PI)
  • Landreth, Gary (PI)
  • Fagan, Joseph (PI)
  • Unnerstall, James (PI)
  • Harik, Sami (PI)
  • Caplan, Arnold I. (PI)
  • Civil, Richard (PI)
  • Whitehouse, Peter (PI)
  • Ripich, Danielle (PI)
  • Friedland, Robert (PI)
  • Gilmore, Grover (PI)
  • Kalaria, Rajesh (PI)
  • Anetzberger, Georgia (PI)
  • Mc Clendon, Mckee (PI)
  • Lamb, Bruce (PI)
  • Whitlatch, Carol J. (PI)
  • Herrup, Karl (PI)
  • Landreth, Gary (PI)
  • Stuckey, Jon C. (PI)
  • Geldmacher, David (PI)
  • Perry, George (PI)
  • Younkin, Steven G (PI)

Project: Research project

Project Details


The research proposed in this project is directed at developing a series
of animals models for Alzheimer's disease using the technology of
transgenic mouse production. The value of such a model is that it would
allow various hypotheses concerning the biological and molecular bases of
the disease to be tested in a reproducible, genetically uniform system.
No such system exists at present and its introduction would speed the
development of new diagnostic tools as well as novel therapeutic
treatments. The specific mice to be created have been chosen based on
evidence that points to the central role of the beta-amyloid precursor
protein in the development of AD. Four types of mice will be produced.
The first type will carry an artificial construct known as LC99 in which
a truncated betaAPP cDNA (missing all coding sequences between the leader
sequence and the last 99 amino acids) is driven by the cytomegalovirus
promoter. Since CMV is a strong promoter with little tissue specificity,
this construct should produce its amyloidogenic fragment promiscuously
throughout the mouse. The specific cleavage products of LC99 have been
well characterized in vitro and it will be informative to determine how
the tissues of the live mouse deal with similar artificial peptides. The
other three transgenic constructs will be driven by the Thy-1 promoter
developed in our laboratory. This promoter drives expression of foreign
genes in most CNS neurons and in a population of perivascular astrocytes.
We will use this tissue specific pattern of expression to drive three
different coding sequences: i) the LC99 sequences for comparison with the
first experiment, ii) the val7l7 -> ile mutation of the betaAPP695 cDNA
and iii) the wild-type form of betaAPP695. The second construct is
identical to the mutation discovered by Hardy in association with a
dominant form of familial Alzheimer's disease and should provide an
increased likelihood of detecting neuropathological changes in the brains
of the mice that carry it. The third construct is meant to serve as a
control to the Hardy mutation lines, allowing us to assess the impact of
the mutation itself. The analyses we will perform are biochemical and
morphometric. Our goal is to thoroughly analyze, with rigorous
quantitative methods, each transgenic line that we create in order to
avoid missing lesions that might be subtle but important, and to prevent
premature claims of a perfect animal model. The three co-investigators
of this project have complementary areas of expertise that should ensure
steady progress towards the goal of creating useful animal models of
Alzheimer's disease.
Effective start/end date9/21/885/31/07


  • Medicine(all)


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