• Younkin, Steven G (PI)
  • Gambetti, Pierluigi (PI)
  • Cohen, Mark (PI)
  • Leblanc, Andrea (PI)
  • Perry, George (PI)
  • Leblanc, Andrea (PI)
  • Cohen, Mark (PI)
  • Gambetti, Pierluigi (PI)

Project: Research project

Project Details


This Lead Award application proposes a major expansion and deepening of the
research currently pursued on Alzheimer disease (AD) at the institution of
the Senior Investigator (SI). It includes four research projects, one by
the SI and three by junior investigators. Four pilot projects are also
presented. They propose innovative research which may open novel
approaches or lead to a breakthrough in AD research. Project 1 by the SI, is a systematic study of the heat shock protein (HSP)
system, beta amyloid precursor protein (betaAPP) and of the ubiquitin
system in the nervous system with the overall aim to establish the role of
HSP and Ub systems in AD and to assess whether betaAPP is expressed as a
HSP. Five sets of studies are proposed: 1) Response of HSP, betaAPP and
Ub as well as the formation of Ub conjugates in neurons, astrocytes and
microglial cells to heat shock and other stress conditions. 2) Effect of
aging on these responses. 3) Role of HSP, betaAPP and Ub in the formation
of neurofibrillary inclusions and dystrophic neurites. 4) Unidentified HSP
which may play a role in AD. 5) Ub conjugates forming under normal and
pathological conditions mimicking the cytoskeletal and neuritic alterations
of AD. Project 2 deals with expression regulation of HSP, betaAPP and Ub in normal
and experimental conditions as well as in AD and related disorders. The
following questions are investigated: 1) Is expression regulation of HSP
and Ub different in neurons, astrocytes and microglia? 2) How is
expression of these proteins and of betaAPP regulated in experimental
models reproducing lesions similar to those of AD? 3) Is expression of
these proteins altered in AD, Pick's disease and Progressive Supranuclear
Palsy? Project 3 focuses on amyloid formation. It evaluates expression of betaAPP
in the non-neuronal cells surrounding senile plaques (SP) using intact
tissue and culture systems. Processing of betaAPP will be analyzed in
culture systems of astrocytes and microglial cells exposed to various forms
of purified betaAPP. Project 4 will answer the following questions: 1) Are straight filaments
(SF) and paired helical filaments (PHF) in continuity with each other and
with neurofilaments and microtubules? 2) Are Ub conjugates present in
dystrophic neurites of SP located in SF and PHF only, or also in membranous
structures? 3) Which cells are involved in the early stages of amyloid
deposition in SP and vessels? 4) Is tubulin present in PHF? The four Pilot Projects deal with: a) a novel method of solubilization of
PHF; b) analysis of cerebrospinal fluid proteases involved in cleavage of
betaAPP; c) substraction hybridization as a technique to identify putative
AD genes on chromosome 21; d) an attempt to produce PHF experimentally. Altogether the projects proposed in this LEAD Award application strengthen
and expand in a major way research on AD carried out under the SI's overall
leadership. They will add novel areas of research which take advantage of
new technologies, they will foster further development of junior
investigators already committed to research in AD and will introduce new
talented investigators to this field of research.
Effective start/end date7/1/916/30/99


  • Medicine(all)