Increased in Vivo Amyloid- 42 Production, Exchange, and Loss in Presenilin Mutation Carriers

Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Science translational medicine (Impact Factor: 15.84). 06/2013; 5(189):189ra77. DOI: 10.1126/scitranslmed.3005615
Source: PubMed


Alzheimer's disease (AD) is hypothesized to be caused by an overproduction or reduced clearance of amyloid-β (Aβ) peptide. Autosomal dominant AD (ADAD) caused by mutations in the presenilin (PSEN) gene have been postulated to result from increased production of Aβ42 compared to Aβ40 in the central nervous system (CNS). This has been demonstrated in rodent models of ADAD but not in human mutation carriers. We used compartmental modeling of stable isotope labeling kinetic (SILK) studies in human carriers of PSEN mutations and related noncarriers to evaluate the pathophysiological effects of PSEN1 and PSEN2 mutations on the production and turnover of Aβ isoforms. We compared these findings by mutation status and amount of fibrillar amyloid deposition as measured by positron emission tomography (PET) using the amyloid tracer Pittsburgh compound B (PIB). CNS Aβ42 to Aβ40 production rates were 24% higher in mutation carriers compared to noncarriers, and this was independent of fibrillar amyloid deposits quantified by PET PIB imaging. The fractional turnover rate of soluble Aβ42 relative to Aβ40 was 65% faster in mutation carriers and correlated with amyloid deposition, consistent with increased deposition of Aβ42 into plaques, leading to reduced recovery of Aβ42 in cerebrospinal fluid (CSF). Reversible exchange of Aβ42 peptides with preexisting unlabeled peptide was observed in the presence of plaques. These findings support the hypothesis that Aβ42 is overproduced in the CNS of humans with PSEN mutations that cause AD, and demonstrate that soluble Aβ42 turnover and exchange processes are altered in the presence of amyloid plaques, causing a reduction in Aβ42 concentrations in the CSF.

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Available from: Kevin E Yarasheski, May 23, 2014
    • "For instance, it is assumed that different Aβs are generated independently from each other (Potter et al., 2013), which is not in line with the current knowledge showing that consecutive γ-secretase cleavages generate Aβ peptides (Takami et al., 2009). Furthermore , we would like to draw attention to the heterogeneous behavior of the mutation carrier cohort, reported as a proof of concept in Potter et al. (2013): the Aβ42 production rates were actually only elevated in three out of seven FAD-linked PSEN mutation carriers. "
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    ABSTRACT: Presenilin (PSEN) pathogenic mutations cause familial Alzheimer's disease (AD [FAD]) in an autosomal-dominant manner. The extent to which the healthy and diseased alleles influence each other to cause neurodegeneration remains unclear. In this study, we assessed gamma-secretase activity in brain samples from 15 nondemented subjects, 22 FAD patients harboring nine different mutations in PSEN1, and 11 sporadic AD (SAD) patients. FAD and control brain samples had similar overall gamma-secretase activity levels, and therefore, loss of overall (endopeptidase) gamma-secretase function cannot be an essential part of the pathogenic mechanism. In contrast, impaired carboxypeptidase-like activity (gamma-secretase dysfunction) is a constant feature in all FAD brains. Significantly, we demonstrate that pharmacological activation of the carboxypeptidase-like gamma-secretase activity with gamma-secretase modulators alleviates the mutant PSEN pathogenic effects. Most SAD cases display normal endo- and carboxypeptidase-like gamma-secretase activities. However and interestingly, a few SAD patient samples display gamma-secretase dysfunction, suggesting that gamma-secretase may play a role in some SAD cases. In conclusion, our study highlights qualitative shifts in amyloid-beta (Abeta) profiles as the common denominator in FAD and supports a model in which the healthy allele contributes with normal Abeta products and the diseased allele generates longer aggregation-prone peptides that act as seeds inducing toxic amyloid conformations.
    No preview · Article · Oct 2015 · Journal of Experimental Medicine
    • "Feeding the in vivo metabolic labeling patient data into a mathematical model, specifically generated for their approach, they described higher Aβ42 production rates in the central nervous system of PSEN mutation carriers (Potter et al., 2013). Accordingly , Potter et al. (2013) suggest that increments in Aβ42 play a decisive pathogenic role in AD. "

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    • "Individuals who were either presenilin mutation negative or mutation positive but negative for amyloid deposition by PiB-PET did not show attenuation of CSF Ab diurnal rhythms, whereas individuals who were presenilin positive and positive for amyloid deposition did show attenuation (Roh et al., 2012). Further, a recent study modeling Ab42 kinetics in presenilin mutation carriers versus noncarriers found that the fractional turnover rate of soluble Ab42 relative to Ab40 was faster in mutation carriers and correlated with amyloid deposition, which is consistent with increased deposition of Ab42 into plaques leading to reduced recovery of Ab42 in CSF (Potter et al., 2013). Extrapolating to sporadic AD, this finding may account for decreased Ab42 levels in individuals with amyloid deposition. "
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    ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline that is a growing public health crisis with a prevalence projected to more than double in the next 20 years. Sleep is frequently impaired in individuals with AD. Further, recent studies have linked numerous age-related sleep disturbances such as poor sleep efficiency and sleep apnea, to future risk of cognitive impairment. Aggregation of amyloid-β (Aβ) into extracellular plaques in the brain is a key step in AD pathogenesis and likely begins 20 years before the onset of dementia. Aβ concentrations in both humans and mouse models show Aβ concentrations rise during wakefulness and fall during sleep, that is, an Aβ diurnal pattern. There is evidence in animal models that changes in sleep time alter Aβ deposition, suggesting that sleep may play a role in AD pathogenesis. A hypothetical model for the role of sleep and the Aβ diurnal pattern in AD pathogenesis is proposed.
    Full-text · Article · May 2014 · Neurobiology of Aging
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