Neuronal exosomes reveal Alzheimer's disease biomarkers in Down syndrome

Hamlett, Eric D.; Goetzl, Edward J.; Ledreux, Aurélie; Vasilevko, Vitaly; Boger, Heather A.; LaRosa, Angela; Clark, David G.; Carroll, Steven L.; Carmona-Iragui, María; Fortea, Juan; Mufson, Elliott J.; Sabbagh, Marwan; Mohammed, Abdul K.; Hartley, Dean M.; Doran, Eric; Lott, Ira T.; Granholm, Ann Charlotte

doi:10.1016/j.jalz.2016.08.012

Cited by 104 publications

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“…This assumption was based on previous work by others, showing increased production of exosomes from cells exposed to amyloid in vitro (Chiarini et al, 2017). To test our hypothesis, we isolated neuron-derived exosomes as previously described (Hamlett et al 2016), and quantified CD81 by enzyme-linked immunosorbent assay (ELISA) (Cusabio, Waltham, MA) against a standard curve of recombinant CD81 (Origene Technologies, Rockville, MD). Briefly, plasma samples were incubated with protease and phosphatase inhibitor cocktails, centrifuged, and the supernatants were mixed with ExoQuick polymer solution (System Bioscience, Mountain view, CA) and incubated at 4°C for 1 h to precipitate exosomes (Hamlett et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…To test our hypothesis, we isolated neuron-derived exosomes as previously described (Hamlett et al 2016), and quantified CD81 by enzyme-linked immunosorbent assay (ELISA) (Cusabio, Waltham, MA) against a standard curve of recombinant CD81 (Origene Technologies, Rockville, MD). Briefly, plasma samples were incubated with protease and phosphatase inhibitor cocktails, centrifuged, and the supernatants were mixed with ExoQuick polymer solution (System Bioscience, Mountain view, CA) and incubated at 4°C for 1 h to precipitate exosomes (Hamlett et al, 2016). The two cohorts included a population of participants with DS (8-62 years old) and a population of age-matched control participants (8-77 years old).…”

Section: Introductionmentioning

confidence: 99%

“…The two cohorts included a population of participants with DS (8-62 years old) and a population of age-matched control participants (8-77 years old). Both populations were age- and gender-matched (Hamlett et al 2016). …”

Section: Introductionmentioning

confidence: 99%

“…To isolate neuron-derived exosomes, samples were incubated with mouse biotinylated anti-human CD171 monoclonal antibody (clone 5G3, neural cell adhesion molecule L1 [L1CAM], eBioscience, San Diego, CA), allowing isolation of only neuron-derived exosomes from the plasma sample (Hamlett et al, 2016; Kapiogannis et al, 2014). We quantified the CD81 levels in neuron-derived exosomes from both DS and control populations (Figure 1B) and found that the neuron-derived exosomes from participants with DS had 39% higher average levels (1,433 ± 87 pg/ml) of the CD81 exosomal marker relative to neuron-derived exosomes from the control participants (1,027 ± 87 pg/ml).…”

Section: Introductionmentioning

confidence: 99%

“…In our collaborative study with several other research groups, we hypothesized that neuron-derived exosomes from blood from people with DS would have elevated levels of Aβ peptides and phosphorylated-Tau (P-Tau) relative to those from controls, which could represent a preclinical phase of AD in DS (Hamlett et al 2016). As described in Hamlett et al (2016), we compared levels of AD biomarkers in neuron-derived exosomes obtained from plasma from a population of participants with DS (8-62 years old) compared to a population of control participants (8-77 years old). The two groups were age- and gender-matched.…”

Section: Introductionmentioning

confidence: 99%

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Exosomal biomarkers in Down syndrome and Alzheimer's disease

Hamlett

Ledreux

Potter³

et al. 2018

Free Radical Biology and Medicine

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Every person with Down syndrome (DS) has the characteristic features of Alzheimer’s disease (AD) neuropathology in their brain by the age of forty, and most go on to develop AD dementia. Since people with DS show highly variable levels of baseline function, it is often difficult to identify early signs of dementia in this population. The discovery of blood biomarkers predictive of dementia onset and/or progression in DS is critical for developing effective clinical diagnostics. Our recent studies show that neuron-derived exosomes, which are small extracellular vesicles secreted by most cells in the body, contain elevated levels of amyloid-beta peptides and phosphorylated-Tau that could indicate a preclinical AD phase in people with DS starting in childhood. We also found that the relative levels of these biomarkers were altered following dementia onset. Exosome release and signaling are dependent on cellular redox homeostasis as well as on inflammatory processes, and exosomes may be involved in the immune response, suggesting a dual role as both triggers of inflammation in the brain and propagators of inflammatory signals between brain regions. Based on recently reported connections between inflammatory processes and exosome release, the elevated neuroinflammatory state observed in people with DS may affect exosomal AD biomarkers. Herein, we discuss findings from studies of people with DS, people with DS and AD (DS-AD), and mouse models of DS showing new connections between neuroinflammatory pathways, oxidative stress, exosomes, and exosome-mediated signaling, which may inform future AD diagnostics, preventions, and treatments in the DS population as well as in the general population.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Exosomal biomarkers in Down syndrome and Alzheimer's disease

Hamlett

Ledreux

Potter³

et al. 2018

Free Radical Biology and Medicine

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Neural-Derived Extracellular Vesicles in Clinical Trials

Dubal

Pleasure

2019

JAMA Neurol

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Association of Extracellular Vesicle Biomarkers With Alzheimer Disease in the Baltimore Longitudinal Study of Aging

et al. 2019

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IMPORTANCE Blood biomarkers able to diagnose Alzheimer disease (AD) at the preclinical stage would enable trial enrollment when the disease is potentially reversible. Plasma neuronal-enriched extracellular vesicles (nEVs) of patients with AD were reported to exhibit elevated levels of phosphorylated (p) tau, Aβ42, and phosphorylated insulin receptor substrate 1 (IRS-1). OBJECTIVE To validate nEV biomarkers as AD predictors. DESIGN, SETTING, PARTICIPANTS This case-control study included longitudinal plasma samples from cognitively normal participants in the Baltimore Longitudinal Study of Aging (BLSA) cohort who developed AD up to January 2015 and age-and sex-matched controls who remained cognitively normal over a similar length of follow-up. Repeated samples were blindly analyzed over 1 year from participants with clinical AD and controls from the Johns Hopkins Alzheimer Disease Research Center (JHADRC). Data were collected from September 2016 to January 2018. Analyses were conducted in March 2019. MAIN OUTCOMES AND MEASURES Neuronal-enriched extracellular vesicles were immunoprecipitated; tau, Aβ42, and IRS-1 biomarkers were quantified by immunoassays; and nEV concentration and diameter were determined by nanoparticle tracking analysis. Levels and longitudinal trajectories of nEV biomarkers between participants with future AD and control participants were compared. RESULTS Overall, 887 longitudinal plasma samples from 128 BLSA participants who eventually developed AD and 222 age and sex-matched controls who remained cognitively normal were analyzed. Participants were followed up (from earliest sample to AD symptom onset) for a mean (SD) of 3.5 (2.31) years (range, 0-9.73 years). Overall, 161 participants were included in the training set, and 80 were in the test set. Participants in the BLSA cohort with future AD (mean [SD] age, 79.09 [7.02] years; 68 women [53.13%]) had longitudinally higher p-tau181, p-tau231, pSer312-IRS-1, pY-IRS-1, and nEV diameter than controls (mean [SD] age, 76.2 [7.36] years; 110 women [50.45%]) but had similar Aβ42, total tau, TSG101, and nEV concentration. In the training BLSA set, a model combining preclinical longitudinal data achieved 89.6% area under curve (AUC), 81.8% sensitivity, and 85.8% specificity for predicting AD. The model was validated in the test BLSA set (80% AUC, 55.6% sensitivity, 88.7% specificity). Preclinical levels of nEV xbiomarkers were associated with cognitive performance. In addition, 128 repeated samples over 1 year from 64 JHADRC participants with clinical AD and controls were analyzed. In the JHADRC cohort (35 participants with AD: mean [SD] age, 74.03 [8.73] years; 18 women [51.43%] and 29 controls: mean [SD] age, 72.14 [7.86] years; 23 women [79.31%]), nEV biomarkers achieved discrimination with 98.9% AUC, 100% sensitivity, and 94.7% specificity in the training set and 76.7% AUC, 91.7% sensitivity, and 60% specificity in the test set. CONCLUSIONS AND RELEVANCE We validated nEV biomarker candidates and further demonstrated that their preclinical longitud...

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Neuronal exosomes reveal Alzheimer's disease biomarkers in Down syndrome

Cited by 104 publications

References 44 publications

Exosomal biomarkers in Down syndrome and Alzheimer's disease

Exosomal biomarkers in Down syndrome and Alzheimer's disease

Neural-Derived Extracellular Vesicles in Clinical Trials

Association of Extracellular Vesicle Biomarkers With Alzheimer Disease in the Baltimore Longitudinal Study of Aging

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