medwireNews: Slowed amyloid-beta turnover may explain aging’s association with increased amyloidosis and Alzheimer’s disease (AD), say researchers.
They found that increasing age was significantly correlated with reduced clearance of amyloid-beta from the central nervous system (CNS), with the half-life increasing 2.5-fold over 5 decades.
This equates to people in their 30s typically taking about 4 hours to clear half the amyloid-beta 42 from the brain, whereas it takes more than 10 hours for those over 80 years of age, explained author Randall Bateman, from Washington University in St Louis, Missouri, USA, in a press release.
This slowing of amyloid-beta clearance from the CNS increases levels of amyloid-beta in the brain and thereby the likelihood of aggregation and amyloidosis, which then greatly increases the risk of cognitive decline and AD, he added.
Bateman and fellow investigators found that the correlation between age and amyloid-beta turnover, as measured in 100 individuals ranging in age from 60 to 87 years, was consistent across amyloid-beta 38, 40 and 42.
Stable isotope labelling kinetics was used to measure amyloid-beta turnover, with the participants receiving a 9-hour infusion of [13C6]leucine to label newly synthesized proteins, including amyloid-beta 38, 40 and 42, which were then sampled in the cerebral spinal fluid for 36 hours.
Comparisons between the 51 patients who were amyloid negative and the 49 who tested positive showed that the time courses for amyloid-beta 38, 40 and 42 were similar in amyloid-negative patients. But in amyloid-positive patients, amyloid-beta 42 labelling kinetics peaked significantly earlier than those for amyloid-beta 38 and 40.
The major kinetic alterations in amyloid-beta 42 in the presence of amyloidosis were increased irreversible loss and reversible exchange, increasing the time that amyloid-beta 42 is present in the CNS. Specifically, amyloid-positive patients had a fractional turnover rate (FTR) of soluble amyloid-beta 42 that was more than 50% faster than that of amyloid-negative patients (0.112 vs 0.094 pools/hour) and a 10-fold higher reversible exchange rate (0.049 vs 0.006 pools/hour).
This reduced clearance of amyloid-beta 42 in the presence of amyloidosis was also significantly associated with cognitive impairment, notes the team.
FTRs for amyloid-beta 42 were significantly faster in amyloid-positive patients who were cognitively healthy than in amyloid-negative patients who were cognitively healthy and cognitively impaired participants irrespective of amyloid status, whereas there was no interaction between cognitive status and amyloid status in the amyloid-beta 42 exchange process.
The researchers therefore propose in the Annals of Neurology that the reduced clearance of amyloid-beta 42 is likely to result from active deposition into amyloid plaques.
From their model, the team estimates that amyloid-beta 42 would need to accumulate for approximately 40 years to reach the levels of amyloidosis typical of AD.
“These findings provide a first link between aging, [amyloid-beta] kinetics, and amyloidosis that will assist in the design of observational and interventional studies in AD”, say Bateman et al.
They add that they also “provide a framework for studying protein kinetics and physiological changes in aging and disease states.”
By Lucy Piper
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