Increased in vivo amyloid-β42 production, exchange, and loss in presenilin mutation carriers

Abstract

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.

Fig. 1. PET images and isotopic enrichment time course profiles of CSF Aβ peptides

(A) Composite PET images showing [¹¹C]Pittsburgh compound B binding in participants who are non-carriers of PSEN mutations (left column), and PSEN mutation carriers who lack (PIB−, middle column) or have (PIB+, right column) evidence of amyloidosis. (B, C) Average Aβ isotopic kinetic time course profiles in CSF showing the Aβ42:40, Aβ38:40, and Aβ42:38 isotopic enrichment ratios (B, middle panel: Aβ38:40, blue circles, Aβ42:38 green squares, and Aβ42:40 red triangles) and as enrichment ratios normalized to plasma leucine plateau enrichments (C, lower panel: Aβ38 blue circles, Aβ40 green squares, Aβ42 red triangles). Aβ38 and Aβ40 present similar labeling profiles in all subject groups, whereas Aβ42 kinetics deviate from Aβ38 and Aβ40 only in mutation carriers, as evident in the Aβ42:40 and Aβ42:38 ratio profiles. Data points represent the mean ± SD for group-averaged values, and the solid lines represent the model fits to the data using the model in Fig. 2.

Fig. 2. Schematic diagram of compartmental model of Aβ38, Aβ40, and Aβ42 metabolism

Solid black triangles depict sampling sites for plasma leucine and CSF Aβ peptides. Production of Aβ peptides is signified by yellow arrows, exchange by blue arrows, and irreversible loss by red arrows. The model incorporated the labeling time course of plasma ¹³C₆-leucine, APP production and processing to C99 peptide, and Aβ38, Aβ40, or Aβ42 production from C99. The labeled Aβ38, Aβ40, and Aβ42 that are sampled in CSF are presumed to be soluble within the “brain” compartment. The soluble Aβ peptides may exchange with other unlabeled Aβ structures, may be transported to CSF, or may be lost due to other processes (e.g. transport to blood, plaque deposition, or cellular degradation). Transport through CSF is modeled as a three compartment time delay.

Fig. 3. Aβ concentrations and selected kinetic parameters

Parameters for Aβ production rate (A), fractional turnover rate (FTR) (B), and baseline CSF concentrations (C) are shown for each group by mutation status and without (PIB−) or with (PIB+) evidence of amyloid deposition. Each parameter was measured for Aβ38 (1^st column), Aβ40 (2^nd column), Aβ42 (3^rd column) and the Aβ42: Aβ40 ratio (4^th column), and compared by mutation status and amyloid deposition. Error bars indicate 95% confidence intervals (CI). Mutation status compared when amyloid deposition did not affect magnitude or significance. * P<0.05, ** P<0.01, *** P<0.001, p-values by ANOVA based on mutation status with PIB MCBP score as a covariate. Non-carriers, blue circles; mutation carriers PIB− (MC PIB−), green squares; mutation carriers PIB+ (MC PIB+), red triangles. Each point represents one participant.

Fig. 4

Potential scheme for the time course of plaque deposition in ADAD. The solid black line signifies “normal” for each measure. The production rate of Aβ42 relative to Aβ40 (gold) remains constant throughout life before and during plaque deposition (production rate was different by mutation status but not by amyloid deposition). CSF concentration of Aβ42 (blue) starts elevated above normal due to overproduction, then decreases to below normal due to an increase in the fractional turnover rate (FTR; red) of Aβ42 relative to Aβ40. As the amount of amyloid plaques increases over time (green), the extent of Aβ42 exchange (dotted) may precede (e.g. if due to oligomer formation), follow closely, or lag behind amyloid deposition (e.g. if due to reversible interaction with amyloid plaques).