# BETA AMYLOID PRECURSOR BINDING TO MOLECULAR CHAPERONES

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 1993 · $215,241

## Abstract

The unique neuropathologic abnormality in Alzheimer's disease is the high
density of neurofibrillar plaques which are formed by the deposition of a
subset of peptides and protein fragments inside and outside of neural
cells.  Among these peptides is a 42 residue fragment of a larger protein,
771 residues in length, termed amyloid precursor protein (APP).  At the
present time there is little understanding of the molecular events in the
formation of these neurofibrillar plaques.  A transmembrane region of APP
constitutes part of the amyloid protein found in plaques.  Furthermore,
little information is currently available to address the manner in which
APP, a cell surface protein, is normally translocated, folded and assembled
with its molecular partners in the cell.  APP is likely synthesized and
translocated through the normal secretory pathway of the cell.  This
requires the active participation of molecular chaperones to mediate
correct folding and assembly events.  The role of these protein folding
catalysts in the biogenesis of APP becomes significant with the observation
that a member of the protein chaperone family, a homologue of E. coli dnaJ,
is associated with neurofibrillar plaques from Alzheimer's tissues.

In the proposed studies, we shall directly examine the interaction of
eukaryotic members of the E. coli dnaK, dnaJ and grpE (KJE) family of
molecular chaperones with unfolded proteins and purified APP.  Using
purified eukaryotic members of this family, including the neuro specific
dnaJ homologue from neurofibrillar plaques, we shall establish the order of
addition, mechanism and energetics of the association of the chaperones
with APP and also examine the regions of APP which may serve as targets for
the binding of members of the KJE homologous.  In preliminary studies, we
have demonstrated that the neuro specific dnaJ homologue termed HSJ1 can
replace the essential homologous protein in the simple eukaryote,
Saccharomyces cerevisiae to restore viability to cells.  To examine the in
vivo consequences of limiting chaperone action on APP aggregation and
processing in cells, we shall establish a model system in yeast to express
either full length APP or portions associated with neurofibrillar ,plaques
in cells harboring conditional mutations in components of the KJE family.
These combined studies would provide the first direct test of the extent to
which these molecular chaperones participate in normal APP biogenesis and
if a reduced role for protein folding catalysts might accelerate amyloid
plaque formation.

## Key facts

- **NIH application ID:** 3123440
- **Project number:** 5R01AG011527-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **SAM.gov UEI:** D3LHU66KBLD5
- **Principal Investigator:** MICHAEL G DOUGLAS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $215,241
- **Award type:** 5
- **Project period:** 1992-09-30 → 1995-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3123440

## Citation

> US National Institutes of Health, RePORTER application 3123440, BETA AMYLOID PRECURSOR BINDING TO MOLECULAR CHAPERONES (5R01AG011527-02). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3123440. Licensed CC0.

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