TY - JOUR
T1 - Amyloid-β Plaques in clinical Alzheimer's disease brain incorporate stable isotope tracer in vivo and exhibit nanoscale heterogeneity
AU - Wildburger, Norelle C.
AU - Gyngard, Frank
AU - Guillermier, Christelle
AU - Patterson, Bruce W.
AU - Elbert, Donald
AU - Mawuenyega, Kwasi G.
AU - Schneider, Theresa
AU - Green, Karen
AU - Roth, Robyn
AU - Schmidt, Robert E.
AU - Cairns, Nigel J.
AU - Benzinger, Tammie L.S.
AU - Steinhauser, Matthew L.
AU - Bateman, Randall J.
N1 - Publisher Copyright:
© 2018 Wildburger, Gyngard, Guillermier, Patterson, Elbert, Mawuenyega, Schneider, Green, Roth, Schmidt, Cairns, Benzinger, Steinhauser and Bateman.
PY - 2018/3/22
Y1 - 2018/3/22
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - Aβ plaques
KW - Plaque dynamics
KW - SILK-SIMS
KW - Stable isotope tracer
UR - http://www.scopus.com/inward/record.url?scp=85044390781&partnerID=8YFLogxK
U2 - 10.3389/fneur.2018.00169
DO - 10.3389/fneur.2018.00169
M3 - Article
C2 - 29623063
AN - SCOPUS:85044390781
SN - 1664-2295
VL - 9
JO - Frontiers in Neurology
JF - Frontiers in Neurology
IS - MAR
M1 - 169
ER -