# APP MRNA DYSREGULATION AND ALZHEIMER'S DISEASE

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 1993 · $115,109

## Abstract

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder which
culminates in senile dementia.  The etiology of AD is unknown although a
variety of data suggests that excessive extracellular deposition of amyloid
beta/A4 protein preceded by intracellular accumulation of its coding mRNA
may be important.  Nucleotide sequence analysis of amyloid protein
precursor (APP) -695, 714, 751 and 770 mRNAs reveals the presence of 4
reiterations of the destabilizing pentanucleotide motif adenosine-uridine-
uridine-uridine-adenosine (AUUUA) which targets cytokine and oncogene mRNAs
for rapid, cytoplasmic degradation.  We have recently identified a novel,
cytoplasmic protein which specifically binds to the AUUUA elements of
cytokine and oncogene mRNAs.  This protein (which we have denoted as the
adenosine-uridine binding factor or AUBF) is upregulated through
phosphorylation by phorbol ester, ionophore or cytokines and likely
participates in the stabilization of cytokine mRNAs by binding to the AUUUA
motifs.  Cytoplasmic lysates from rodent and human brain and a human
neuroblastoma cell line constitutively express AUBF activity as well as
three additional, novel, brain-specific AUUUA binding activities (denoted
AUBF-B).  These activities can be modulated by cytokines and specifically
bind to APP mRNAs through the AUUUA motifs.  Therefore, we hypothesize that
the AUUUA containing APP mRNAs are normally unstable.  The binding of AUBF
or AUBF-B to APP mRNAs through the AUUUA motifs stabilizes the APP message
leading to a relative accumulation of APP mRNA and subsequent APP
production in the brain of AD patients.  Thus the specific aims of this
proposal are to: 1). Establish the turnover rates of the four wild type APP
mRNAs (695, 714, 751, 770) as well as mutated APP transcripts with reduced
numbers of AUUUA motifs after the stable transfection of their coding cDNAs
into a human neuroblastoma cell line (SH-SY-5Y).  The effects of IL-1,
tumor necrosis factor, nerve growth factor and calcium ionophore on the
turnover of wild type and mutant APP mRNAs and the level of AUBF and AUBF-B
activities will be determined; 2). Purify AUBF-B activities from human
brain by RNA affinity chromatography and generate polyclonal and monoclonal
antibodies against these proteins. 3). Employ a cell-free RNA degradation
system derived from rabbit reticulocyte lysate to assess the turnover rates
of wild-type and mutant APP mRNAs; 4). Establish the function of AUBF-B by
adding purified protein(s) the cell-free degradation system followed by
measurement of the turnover rate of wild-type and mutant APP mRNAs.
Cumulatively these studies will clarify the roles of posttranscriptional
gene regulation and AUBF-B in the accumulation of APP mRNAs.

## Key facts

- **NIH application ID:** 3122611
- **Project number:** 5R01AG010675-04
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **SAM.gov UEI:** LCLSJAGTNZQ7
- **Principal Investigator:** James S Malter
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $115,109
- **Award type:** 5
- **Project period:** 1991-09-29 → 1996-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3122611

## Citation

> US National Institutes of Health, RePORTER application 3122611, APP MRNA DYSREGULATION AND ALZHEIMER'S DISEASE (5R01AG010675-04). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3122611. Licensed CC0.

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