Amyloid-β Plaques in clinical Alzheimer's disease brain incorporate stable isotope tracer in vivo and exhibit nanoscale heterogeneity

Norelle C. Wildburger, Frank Gyngard, Christelle Guillermier, Bruce W. Patterson, Donald Elbert, Kwasi G. Mawuenyega, Theresa Schneider, Karen Green, Robyn Roth, Robert E. Schmidt, Nigel J. Cairns, Tammie L.S. Benzinger, Matthew L. Steinhauser, Randall J. Bateman

Research output: Contribution to journalArticle

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder with clinical manifestations of progressive memory decline and loss of executive function and language. AD affects an estimated 5.3 million Americans alone and is the most common form of age-related dementia with a rapidly growing prevalence among the aging population-those 65 years of age or older. AD is characterized by accumulation of aggregated amyloid-beta (Aβ) in the brain, which leads to one of the pathological hallmarks of AD-Aβ plaques. As a result, Aβ plaques have been extensively studied after being first described over a century ago. Advances in brain imaging and quantitative measures of Aβ in biological fluids have yielded insight into the time course of plaque development decades before and after AD symptom onset. However, despite the fundamental role of Aβ plaques in AD, in vivo measures of individual plaque growth, growth distribution, and dynamics are still lacking. To address this question, we combined stable isotope labeling kinetics (SILK) and nanoscale secondary ion mass spectrometry (NanoSIMS) imaging in an approach termed SILK-SIMS to resolve plaque dynamics in three human AD brains. In human AD brain, plaques exhibit incorporation of a stable isotope tracer. Tracer enrichment was highly variable between plaques and the spatial distribution asymmetric with both quiescent and active nanometer sub-regions of tracer incorporation. These data reveal that Aβ plaques are dynamic structures with deposition rates over days indicating a highly active process. Here, we report the first, direct quantitative measures of in vivo deposition into plaques in human AD brain. Our SILK-SIMS studies will provide invaluable information on plaque dynamics in the normal and diseased brain and offer many new avenues for investigation into pathological mechanisms of the disease, with implications for therapeutic development.

LanguageEnglish (US)
Article number169
JournalFrontiers in Neurology
Volume9
Issue numberMAR
DOIs
StatePublished - Mar 22 2018

Fingerprint

Amyloid Plaques
Isotopes
Alzheimer Disease
Brain
Isotope Labeling
Secondary Ion Mass Spectrometry
Executive Function
Memory Disorders
Brain Diseases
Growth
Amyloid
Neuroimaging
Neurodegenerative Diseases
Dementia
Language

Keywords

  • Alzheimer's disease
  • Aβ plaques
  • Plaque dynamics
  • SILK-SIMS
  • Stable isotope tracer

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Amyloid-β Plaques in clinical Alzheimer's disease brain incorporate stable isotope tracer in vivo and exhibit nanoscale heterogeneity. / Wildburger, Norelle C.; Gyngard, Frank; Guillermier, Christelle; Patterson, Bruce W.; Elbert, Donald; Mawuenyega, Kwasi G.; Schneider, Theresa; Green, Karen; Roth, Robyn; Schmidt, Robert E.; Cairns, Nigel J.; Benzinger, Tammie L.S.; Steinhauser, Matthew L.; Bateman, Randall J.

In: Frontiers in Neurology, Vol. 9, No. MAR, 169, 22.03.2018.

Research output: Contribution to journalArticle

Wildburger, NC, Gyngard, F, Guillermier, C, Patterson, BW, Elbert, D, Mawuenyega, KG, Schneider, T, Green, K, Roth, R, Schmidt, RE, Cairns, NJ, Benzinger, TLS, Steinhauser, ML & Bateman, RJ 2018, 'Amyloid-β Plaques in clinical Alzheimer's disease brain incorporate stable isotope tracer in vivo and exhibit nanoscale heterogeneity' Frontiers in Neurology, vol. 9, no. MAR, 169. https://doi.org/10.3389/fneur.2018.00169
Wildburger, Norelle C. ; Gyngard, Frank ; Guillermier, Christelle ; Patterson, Bruce W. ; Elbert, Donald ; Mawuenyega, Kwasi G. ; Schneider, Theresa ; Green, Karen ; Roth, Robyn ; Schmidt, Robert E. ; Cairns, Nigel J. ; Benzinger, Tammie L.S. ; Steinhauser, Matthew L. ; Bateman, Randall J. / Amyloid-β Plaques in clinical Alzheimer's disease brain incorporate stable isotope tracer in vivo and exhibit nanoscale heterogeneity. In: Frontiers in Neurology. 2018 ; Vol. 9, No. MAR.
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