ABSTRACT
Down syndrome (DS) is a genetic condition involving an extra copy of chromosome 21 including a triplication of
the APP gene. People with DS have high penetrance of Alzheimer's Disease (AD) pathology with amyloid-beta
(Aß) deposition and intracellular Tau-containing neurofibrillary tangles (NFTs), and is highly correlated with
cognitive impairment in both AD and DS-AD. Metabolomics studies indicate alterations in the polyamine pathway
is involved in both, DS and AD. How polyamines affect the development of DS-AD pathology remains largely
unknown. Our preliminary data using neuronal-derived exosomes from individuals with DS indicates alterations
in the polyamines putrescine, spermine and spermidine. The goal of this application is to understand whether
alterations in polyamine content contribute to the development of AD pathology in DS. The Overall Hypothesis
is that polyamines represent a contributing factor in promoting Aß oligomerization leading to neuronal dysfunction
in DS-AD. To address this hypothesis, we propose 1) to examine polyamine content in individuals with DS, DS-
AD and age matching controls (aged from 8-63) and correlate polyamine levels with AD biomarkers (Tau and
amyloid). Brain tissue, cerebrospinal fluid and neuronal-derived exosomes from blood, will be used to assess
this aim. We will use Micellar Electrokinetic Chromatography with laser induced fluorescence Detection (MEC-
LIFD) to measure polyamine levels and correlate with AD biomarkers to determine whether alterations in
polyamine levels occur in DS. 2) Using a DS cell culture system, we will determine if the overexpression of Aß
leads to alteration in the levels of polyamines, thus promoting the oligomerization of Aß. To accomplish this, we
will use a cortical DS cell culture from Chr. 16 Trisomic mice (CTb). This cell line, which overexpresses APP and
Aß, will be used to determine whether Aß overexpression increases polyamine levels and in turn, if increases in
polyamine content exacerbate Aß aggregate formation in a DS cell line. The idea that polyamines affect
aggregation of amyloid is novel and translational, since there are specific FDA approved drugs which can
modulate the polyamine synthesis. The short term goal of this proposal is to identify polyamines as contributing
factors in the development of DS-AD and AD pathologies. If this is shown to be true, avenues will be open to our
long-term goal, to assess the disease modifying potential of FDA-approved drugs like ornithine decarboxylase
(ODC) inhibitors. This study provides the opportunity to use the polyamine pathway as a potential drug target
that could be a contributing factor in the development of neuropathology underlying dementia in DS-AD.