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 (A?) 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 A?1-42, 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 A?1-42, 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.
Down syndrome leads to Alzheimer's disease with high penetrance and few treatment avenues are available. Our group of researchers is uniquely suited to perform mechanistic studies as well as evaluate biomarkers that will contribute to biomarkers that may help design novel preventive and intervention treatments.
|Hamlett, Eric D; Ledreux, Aurélie; Potter, Huntington et al. (2018) Exosomal biomarkers in Down syndrome and Alzheimer's disease. Free Radic Biol Med 114:110-121|
|Hamlett, Eric D; Goetzl, Edward J; Ledreux, Aurélie et al. (2017) Neuronal exosomes reveal Alzheimer's disease biomarkers in Down syndrome. Alzheimers Dement 13:541-549|