Abstract
The kinetics of amyloid beta turnover within human brain is still poorly understood. We previously found a dramatic decline in the turnover of Aβ peptides in normal aging. It was not known if brain interstitial fluid/cerebrospinal fluid (ISF/CSF) fluid exchange, CSF turnover, blood-brain barrier function or proteolysis were affected by aging or the presence of β amyloid plaques. Here, we describe a non-steady state physiological model developed to decouple CSF fluid transport from other processes. Kinetic parameters were estimated using: (1) MRI-derived brain volumes, (2) stable isotope labeling kinetics (SILK) of amyloid-β peptide (Aβ), and (3) lumbar CSF Aβ concentration during SILK. Here we show that changes in blood-brain barrier transport and/or proteolysis were largely responsible for the age-related decline in Aβ turnover rates. CSF-based clearance declined modestly in normal aging but became increasingly important due to the slowing of other processes. The magnitude of CSF-based clearance was also lower than that due to blood-brain barrier function plus proteolysis. These results suggest important roles for blood-brain barrier transport and proteolytic degradation of Aβ in the development Alzheimer’s Disease in humans.
Highlights
The kinetics of amyloid beta turnover within human brain is still poorly understood
Stable isotope-labeling kinetics (SILK) in humans have previously revealed that: (1) the turnover rate of Aβ42 (FTR42) relative to Aβ40 (FTR40) increases in both sporadic Alzheimer’s disease (AD) and autosomal dominant Alzheimer’s Disease (ADAD), likely due to active deposition of Aβ42 into plaques; (2) the production rate of Aβ42 relative to Aβ40 increases in ADAD; and (3) the turnover rates of amyloid-β peptide (Aβ) peptides decrease with age[1,2,3]
The kinetic models could not account for the effects of secretase inhibitors[4,5,6], or explain the rise in the lumbar cerebrospinal fluid (CSF) concentration of Aβ peptides observed during the 36–48 h stable isotope labeling kinetics (SILK) studies[7,8,9,10]
Summary
Correlation of MRI-derived volumes with age and steady-state model parameters. CNS volumes were recorded by MRI for 100 study subjects who completed SILK kinetic studies, with four subjects excluded due to poor fits of the model to SILK or lumbar concentration data. The mean rate of irreversible loss of Aβ40 peptides by transport across the BBB or via proteolysis is predicted by the physiological model to be 25 ± 28 ng/min (Eq (3)) This is greater than the experimentally measured value from inferior petrosal sinus sampling, suggesting that at least 60% of Aβ40 is cleared from the brain by proteolysis. The fraction of CSF-based clearance significantly increased with age for Aβ38 and Aβ40 in amyloid-negative subjects due to the significant decline in clearance across the blood–brain barrier or by proteolysis ( see Table 1). Much greater clearance of Aβ42 via BBB/proteolysis is found in younger subjects, with a smaller increase in CSF-based clearance These balance the greater rate of production of APP- > C99- > Aβ42, perhaps due to greater neuron number reflected in the larger volume of gray matter or due to greater neuronal activity
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