Mean age-of-onset of familial alzheimer disease caused by presenilin mutations correlates with both increased Aβ42 and decreased Aβ40

Abstract

The varied ways in which mutations in presenilins (PSEN1 and PSEN2) affect amyloid b precursor protein (APP) processing in causing early-onset familial Alzheimer disease (FAD) are complex and not yet properly understood. Nonetheless, one useful diagnostic marker is an increased ratio of Ab42 to Ab40 (Ab42/Ab40) in patients' brain and biological fluids as well as in transgenic mice and cells. We studied Ab and APP processing for a set of nine clinical PSEN mutations on a novel and highly reproducible enzyme-linked immunosorbent assay (ELISA)-based in vitro method and also sought correlation with brain Ab analyzed by image densitometry and mass spectrometry. All mutations significantly increased Ab42/Ab40 in vitro by significantly decreasing Ab40 with accumulation of APP C-terminal fragments, a sign of decreased PSEN activity. A significant increase in absolute levels of Ab42 was observed for only half of the mutations tested. We also showed that age-of-onset of PSEN1-linked FAD correlated inversely with Ab42/Ab40 (r = -0.89; P = 0.001) and absolute levels of Ab42 (r = -0.83; P = 0.006), but directly with Ab40 levels (r = 0.69; P = 0.035). These changes also partly correlated with brain Ab42 and Ab40 levels. Together, our data suggested that Ab40 might be protective by perhaps sequestering the more toxic Ab42 and facilitating its clearance. Also, the in vitro method we describe here is a valid tool for assaying the pathogenic potential of clinical PSEN mutations in a molecular diagnostic setting.

Potent amyloidogenicity and pathogenicity of Aβ43

“…In addition, we observed that a variety of FAD-associated PS1 mutations resulted in overproduction of Aβ43 in a manner correlating with the quantity of Aβ42 as well as with the age of onset of the patients 24 ( Fig. 5 and Supplementary Fig.…”

“…Because Aβ42 is produced independently of Aβ43 in the presence of γ-secretase, some of the FAD-associated PS1 mutations that cause a decrease in Aβ40 without an increase in Aβ42, such as A79V, A231V, C263F, L282V, L166P and G384A 24,38 , might actually result in the elevation of Aβ43 in a manner similar to the R278I mutation. In addition, PS1-ΔE10, an artificial PS1 mutation located to the loop domain of PS1 where R278I is present, showed a significant reduction of the steady state levels of Aβ40 without any alteration of the Aβ42 levels similar to our results, however Aβ43 levels were not measured 39 .…”

“…Figs 6a,b and 7). (c-e) Specificity of the antibodies to Aβ40, Aβ42 24 and Aβ43 used in this ELISA system. Synthetic Aβ1-40, Aβ1-42 and Aβ1-43 were separated by Tris/Tricine PAGE (15% polyacrylamide gel) and subjected to Western blotting.…”

The PSEN1 I143T mutation in a Swedish family with Alzheimer's disease: clinical report and quantification of Aβ in different brain regions

“…The g-secretase complex with the I143T mutation in PSEN1 has been suggested to produce Ab peptides of different lengths. 13 We recently reported that a longer variant, Ab43, is present in plaque cores and in total amyloid preparations obtained from sporadic and familial AD brains, and was indeed found more frequently than Ab40. 14 A quantitative approach was used to study Ab40, Ab42, and Ab43 in two mutation carriers diagnosed with a severe and aggressive form of EOAD by examining samples taken from six brain regions, including the frontal, parietal, temporal, and occipital cortex, as well as anterior hippocampus and cerebellum.…”

Identification of distinct physiochemical properties of toxic prefibrillar species formed by Aβ peptide variants

“…Aβ 42 has a higher propensity to form prefibrillar and fibrillar aggregates than Aβ 40 and has also been reported to be more toxic [4]. Furthermore, it has been shown that an increased ratio of Aβ 42 to Aβ 40 correlates with an increased risk of subsequently developing AD [5]. Monomeric Aβ aggregates into insoluble fibrils via different soluble intermediates [6].…”