Biological Correlates of Alzheimer in Down Syndrome. - ABSTRACT
Down syndrome (DS) is the most common non-lethal aneuploidy in humans, caused by complete or partial
trisomy of chromosome 21. In addition to intellectual disability and atypical development often observed in DS,
the prevalence of dementia is significantly higher, with onset at an earlier age than in the general population. A
strong candidate mechanism is the amyloid beta precursor protein (APP) gene which is located on
chromosome 21 and triplicated in people with DS, giving rise to toxic amyloid peptides at an early age.
Individuals with DS exhibit Alzheimer's disease (AD) neuropathology and dementia early in life. The presence
of AD pathology in younger individuals with DS is relatively unknown, due in part to a paucity of brain tissue
available for study at earlier age epochs. Biomarkers that reflect AD pathology at earlier ages are thus of
considerable interest since neuroprotective therapies will eventually target younger individuals with DS. Most
cell types in the body, including neurons, release small endosomally-derived vesicles, known as exosomes.
Exosomes contain proteins, messenger RNA (mRNA) and microRNA (miRNA) that play a prominent role in
cellular signaling, removal of unwanted proteins, and transfer of cellular pathogens to other cells. Because of
their small size, secreted exosomes diffuse into biological fluids (blood, cerebrospinal fluid (CSF) and urine)
and circulate in the interstitial space, both in the brain and the periphery. Neuronal exosomes have unique
neuron-specific surface markers, which enable targeted examination from circulating biological fluids. We
hypothesize that elevations of amyloid-beta (Aß) peptides and phosphorylated-Tau (P-Tau) in neuronal
exosomes may document preclinical AD in those with DS. In a recent manuscript, we demonstrated that
neuronal exosome levels of Aß1-42, P-T181-Tau and P-S396-Tau were significantly elevated in individuals with
DS compared to age-matched controls at an early age. These early increases in Aß1-42, P-T181-Tau, and P-
S396-Tau in individuals with DS may provide a basis for early intervention as targeted treatments become
available. We wish to continue these preliminary studies by examining AD biomarkers in exosomes in
relationship to cognitive impairment and CSF biomarkers in participants with DS (Aim 1). Further, Tau protein
aggregates into neurofibrillary tangles (NFTs) that progressively spread to synaptically connected brain
regions. A prion-like mechanism has been suggested: misfolded Tau propagating through the brain seeds
neurotoxic aggregation of soluble Tau in recipient neurons. In Aim 2 of this application, we will perform
seeding experiments using exosomes from patients with DS and DS-AD injected into the brain of a DS mouse
model, to determine seeding capacity of Tau species produced in the brain of those with DS. These studies will
lead to more information regarding validity of exosome biomarkers to predict conversion to dementia in DS,
and will also provide novel information regarding mechanistic effects of toxic Tau species in the DS brain.
