Switched A\u03b243 generation in familial Alzheimer\u2019s disease with presenilin 1 mutation

Nobuto Kakuda,Kensaku Kasuga,Mako Takami,Yasuo Ihara,Masayasu Okochi,Takeshi Ikeuchi

doi:10.1038/s41398-021-01684-1

Nobuto Kakuda, Kensaku Kasuga + Show 4 more

Open Access

https://doi.org/10.1038/s41398-021-01684-1

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Abstract

Presenilin (PS) with a genetic mutation generates abundant β-amyloid protein (Aβ) 43. Senile plaques are formed by Aβ43 in the cerebral parenchyma together with Aβ42 at middle ages. These brains cause the early onset of Alzheimer’s disease (AD), which is known as familial Alzheimer’s disease (FAD). Based on the stepwise processing model of Aβ generation by γ-secretase, we reassessed the levels of Aβs in the cerebrospinal fluid (CSF) of FAD participants. While low levels of Aβ38, Aβ40, and Aβ42 were generated in the CSF of FAD participants, the levels of Aβ43 were unchanged in some of them compared with other participants. We sought to investigate why the level of Aβ43 was unchanged in FAD participants. These characteristics of Aβ generation were observed in the γ-secretase assay in vitro using cells, which express FAD mutations in PS1. Aβ38 and Aβ40 generation from their precursors, Aβ42 and Aβ43, was decreased in PS1 mutants compared with wild-type (WT) PS1, as observed in the CSF. Both the ratios of Aβ38/Aβ42 and Aβ40/Aβ43 in PS1 mutants were lower than those in the WT. However, the ratio of Aβ43/amyloid precursor protein intracellular domain (AICD) increased in the PS1 mutants in an onset age dependency, while other Aβ/AICD ratios were decreased or unchanged. Importantly, liquid chromatography–mass spectrometry found that the generation of Aβ43 was stimulated from Aβ48 in PS1 mutants. This result indicates that PS1 mutants switched the Aβ43 generating line, which reflects the level of Aβ43 in the CSF and forming senile plaques.

Highlights

Familial Alzheimer’s disease (FAD) patients are less prevalent than those with sporadic Alzheimer’s disease (AD) [1, 2]
Nishimura and colleagues reported that random mutagenesis generated a PS1 R278I mutation that results exclusively in the production of Aβ43 [15], and Saido and colleagues reported that mutant PS1 transgenic mice (R278I/APPsw) had elevated levels of Aβ43 and earlier formation of senile plaques in their brains [16]
The onset age of these mutations was 27 years for L85P, 49.6 years for G209R, and 29 years for L381V. These results indicate that the levels of Aβ38, Aβ40, and Aβ42 decreased in the cerebrospinal fluid (CSF) of FAD participants, while Aβ43 might be defective by those mutations (Fig. 1B)

Summary

Introduction

Familial Alzheimer’s disease (FAD) patients are less prevalent (approximately 1%) than those with sporadic Alzheimer’s disease (AD) [1, 2]. Nishimura and colleagues reported that random mutagenesis generated a PS1 R278I mutation that results exclusively in the production of Aβ43 [15], and Saido and colleagues reported that mutant PS1 transgenic mice (R278I/APPsw) had elevated levels of Aβ43 and earlier formation of senile plaques in their brains [16]. This particular mutation was identified in a patient who presented with language disturbance [17]. These sequential Aβ generation mechanisms have been referred to as stepwise processing [18,19,20]

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