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. 2013 Feb;125(2):187-99.
doi: 10.1007/s00401-012-1065-6. Epub 2012 Nov 9.

Presenilin-1 adopts pathogenic conformation in normal aging and in sporadic Alzheimer's disease

Lara Wahlster  1 , Muriel Arimon, Navine Nasser-Ghodsi, Kathryn Leigh Post, Alberto Serrano-Pozo, Kengo Uemura, Oksana Berezovska
Affiliations

Presenilin-1 adopts pathogenic conformation in normal aging and in sporadic Alzheimer's disease

Lara Wahlster et al. Acta Neuropathol. 2013 Feb.

Abstract

Accumulation of amyloid-β (Aβ) and neurofibrillary tangles in the brain, inflammation and synaptic and neuronal loss are some of the major neuropathological hallmarks of Alzheimer's disease (AD). While genetic mutations in amyloid precursor protein and presenilin-1 and -2 (PS1 and PS2) genes cause early-onset familial AD, the etiology of sporadic AD is not fully understood. Our current study shows that changes in conformation of endogenous wild-type PS1, similar to those found with mutant PS1, occur in sporadic AD brain and during normal aging. Using a mouse model of Alzheimer's disease (Tg2576) that overexpresses the Swedish mutation of amyloid precursor protein but has normal levels of endogenous wild-type presenilin, we report that the percentage of PS1 in a pathogenic conformation increases with age. Importantly, we found that this PS1 conformational shift is associated with amyloid pathology and precedes amyloid-β deposition in the brain. Furthermore, we found that oxidative stress, a common stress characteristic of aging and AD, causes pathogenic PS1 conformational change in neurons in vitro, which is accompanied by increased Aβ42/40 ratio. The results of this study provide important information about the timeline of pathogenic changes in PS1 conformation during aging and suggest that structural changes in PS1/γ-secretase may represent a molecular mechanism by which oxidative stress triggers amyloid-β accumulation in aging and in sporadic AD brain.

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Figures

Figure 1
Figure 1. PS1 conformational changes occur in sporadic AD
FLIM analysis of different conformational states of PS1 molecules (%EFRET) in CA1 hippocampal neurons in human brain. (a) Bar graph shows average %EFRET and (b) histogram shows distribution of the %EFRET values in sporadic AD (n = 10 cases, total of 477 neurons), non-demented control (n = 10 cases, total of 308 neurons) and FTLD (n = 5 cases, total of 196 neurons) brain tissue (mean ± SD; ***=p<0.001, n.s.= not significant; One-way ANOVA with Bonferroni’s post-hoc correction (a), and Goodness-of-fit test with D’Agostino & Pearson omnibus normality test (b). Arrows in (b) show a subpopulation of neurons with “closed” PS1 conformation. (c) Color-coded FLIM images of representative neurons in CA1 area of AD, control, and FTLD brain samples. Donor fluorophore lifetimes in outlined cells represent different proximity between fluorophore-tagged domains on PS1 molecule, and thus PS1 in different conformations. Colorimetric scale shows fluorescence lifetime in picoseconds. Note: yellow-tored pixels represent PS1 molecules in “closed” conformation.
Figure 2
Figure 2. PS1 conformation correlates with proximity to ThioS positive A plaques
(a) Top panels show Alexa 488 fluorescence intensity image (left) and pseudo-colored FLIM image (right) of a neuron immunostained with Alexa488-labeled PS1 NT and Cy3-labeled PS1 CT antibodies. The pseudo-colored image displays donor fluorophore lifetimes calculated on a pixel-by-pixel basis, with red-to-yellow pixels representing shorter lifetimes. Colorimetric scale shows lifetime in picoseconds. The bottom panel shows a confocal fluorescence intensity image of the same neuron (red box) after ThioS counterstaining to determine its proximity to the A plaque. The distance between neurons and plaques was determined using Zeiss LSM510 software. (b) The scatter diagram shows distribution of the %EFRET values in different neurons relative to their respective distance to the closest plaque (linReg: y=−0.02 X+15.9 with r= −0.49, p<0.0001). (c) The %EFRET values from (b) were grouped and separated in 100 μm intervals to correlate the percent of neurons in “open” and “closed” conformations to A plaque proximity. (mean SD, ***=p<0.001, One way ANOVA).
Figure 3
Figure 3. PS1 conformational changes are associated with aging
FLIM analysis in aging mouse brains reveals CA1 hippocampal neurons with different conformational states of the PS1 molecules. Histograms show distribution of the %E FRET values representing PS1 NT-CT proximity in neurons of Tg2576 (dark grey) and non-transgenic littermate (light grey) mice of different ages: (a) 2–4 months of age, young animals (wt: n = 172 neurons; tg: n = 198 neurons); (b) 7–9 months adult mice (wt: n = 217 neurons; tg: n = 273 neurons); and (c) >17 months of age, old animals (wt: n = 173 neurons; tg: n = 160 neurons) (mean SD; ***=p<0.001, **=p<0.01, ns= not significant; 2-sided student’s t-test or One-way ANOVA with Bonferroni’s post-hoc correction.)
Figure 4
Figure 4. Oxidative stress triggers PS1 conformational changes in vitro
(a) Bar graph shows quantitative analysis of %EFRET values in neurons treated with vehicle, NACA, DTDP, and/or HNE (vehicle: n = 167; NACA-vehicle: n = 216; vehicle-DTDP: n = 115, vehicle-HNE: n = 106; NACA-DTDP: n = 145; NACA-HNE: n = 125 neurons). The data are presented as mean ± SEM; (***p<0.001, **=p<0.01, *=p<0.05, n.s.= not significant; One-way ANOVA with Bonferroni’s post-hoc correction). (b) Representative FLIM images of primary neurons transfected with GFP-PS1-RFP FRET reporter construct, and pretreated with NACA (or vehicle) before exposure to DTDP (or vehicle). The pseudo-colored images display donor fluorophore lifetimes, with yellow-to-red pixels representing PS1 in “closed” conformation. Colorimetric scale shows lifetime in picoseconds.
Figure 5
Figure 5. Effect of oxidative stress on A production
Primary neurons were treated with DTDP, HNE, or vehicle for 3 hours, and the condition media was collected to assess production of A 40 and A 42 by ELISA. The amount of each Aβ species is presented as fold-change after being normalized to that in the conditioned media of vehicle-treated control cells (vehicle: n = 10, DTDP: n = 11, HNE: n = 12 wells, three independent experiments). The data are shown as mean SEM (***p<0.001, **p<0.01, *p<0.05, ns= not significant; Mann Whitney non-parametric t-test).
Figure 6
Figure 6
Schematic representation of the hypothetical interplay between oxidative stress, PS1 conformational changes, and elevated A 42/40 ratio. Elevated level of the oxidative stress (ROS) in the brain may induce local changes in the A 42/40 ratio and amyloidosis by altering conformation of PS1/-secretase. Accumulation of highly fibrillogenic A 42 species, subsequently, may cause oxidative stress, feeding into a positive, feed-forward cycle of deleterious events
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