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BRAIN PROTEOMICS OF COGNITIVELY HEALTHY CENTENARIANS IN THE CONTEXT AGING AND ALZHEIMER’S DISEASE
Abstract
Aims
Some individuals maintain high levels of cognitive health despite reaching extreme ages. To identify molecular mechanisms that confer resilience or resistance to age- or disease-related cognitive decline, we compared the proteome of brain tissues from centenarians with non-demented individuals and Alzheimer’s disease (AD) patients covering an age-continuum of 50-95 years.
Methods
We performed quantitative proteomics on middle temporal lobe tissues collected from 58 centenarians from the 100-plus Study, 61 non-demented individuals and 91 AD patients from the Netherlands Brain Bank. Next, we investigated protein-abundance using age and Braak stages as independent variables and put findings in centenarians in both contexts.
Results
We identified 3,448 proteins across all samples: the expression of 472 proteins associated with Braak stages, and 174 proteins associated with age. The abundance of 13 Braak stage related proteins differed between centenarians and AD cases, including ubiquitin, cytoskeletal- and synaptic proteins. For 97 proteins that associated with increasing age, we observed that expression in cognitively healthy centenarians resembled abundances observed at younger ages (e.g., microtubular, intermediate filament and myelin-associated proteins).
Conclusions
We present a unique view on both aging and AD, attempting to disentangle the effects of the two. We identified unique patterns of regulation of (i) Braak stage-related, (ii) age-related, and (iii) age- and Braak stage-related proteins. The 13 proteins differentially regulated in centenarians compared to AD cases at Braak stage IV, may point to mechanisms involved in resilience against the presence of tangles. In contrast, the 97 differentially regulated aging proteins point towards key mechanisms in brain aging.