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.
Highlights
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by progressive cognitive and functional decline and is the most common form of age-related dementia [1, 2]
To determine whether 13C6-leucine enrichment could be detected in vivo in native Aβ plaques, two individual APP/PS1 mice (3.5 months of age) were administered 13C6-leucine tracer for 10 and 5 weeks (Figure 2A)
Despite being labeled for half the amount of time with an additional 5 weeks of tracer washout, the plaque enrichment was approximately two-thirds of that measured in the 10-week labeled animal (1.6% ± 0.02% vs. 2.4% ± 0.03%)
Summary
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by progressive cognitive and functional decline and is the most common form of age-related dementia [1, 2]. The incidence of AD-related death and disability is rapidly growing in persons 65 years of age or older whose risk of developing the disease doubles every 5 years [3]; currently, an estimated 5.3 million Americans are affected [4]. Abnormal accumulation and aggregation of Aβ in the cerebral extracellular space result in one of the pathological hallmarks of AD—amyloid plaques. Longitudinal measures of amyloid pathology have shown increases in amyloid deposition 15–20 years prior to dementia onset [15] in early onset, familial AD and predict future cognitive decline [16,17,18,19,20]
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