Alternative processing of γ-secretase substrates in common forms of mild cognitive impairment and alzheimer's disease: Evidence for γ-secretase dysfunction

Saori Hata, Sayaka Fujishige, Yoichi Araki, Miyako Taniguchi, Katsuya Urakami, Elaine Peskind, Hiroyasu Akatsu, Masahiko Araseki, Kazuo Yamamoto, Ralph N. Martins, Masahiro Maeda, Masaki Nishimura, Allan Levey, Kathryn (Kathy) Chung, Thomas Montine, James Leverenz, Anne Fagan, Alison Goate, Randall Bateman, David M. HoltzmanTohru Yamamoto, Tadashi Nakaya, Sam Gandy, Toshiharu Suzuki

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Objective: The most common pathogenesis for familial Alzheimer's disease (FAD) involves misprocessing (or alternative processing) of the amyloid precursor protein (APP) by γ-secretase due to mutations of the presenilin 1 (PS1) gene. This misprocessing/alternative processing leads to an increase in the ratio of the level of a minor γ-secretase reaction product (Aβ42) to that of the major reaction product (Aβ40). Although no PS1 mutations are present, altered Aβ42/40 ratios are also observed in sporadic Alzheimer's disease (SAD), and these altered ratios apparently reflect deposition of Aβ42 as amyloid. Methods: Using immunoprecipitation-mass spectrometry with quantitative accuracy, we analyzed in the cerebrospinal fluid (CSF) of various clinical populations the peptide products generated by processing of not only APP but also an unrelated protein, alcadein (Alc). Alc undergoes metabolism by the identical APP α-secretases and γ-secretases, yielding a fragment that we have named p3-Alc α because of the parallel genesis of p3-Alcα peptides and the p3 fragment of APP. As with Aβ, both major and minor p3-Alcαs are generated. We studied the alternative processing of p3-Alcα in various clinical populations. Results: We previously reported that changes in the Aβ42/40 ratio showed covariance in a linear relationship with the levels of p3-Alcα [minor/major] ratio in media conditioned by cells expressing FAD-linked PS1 mutants. Here we studied the speciation of p3-Alcα in the CSF from 3 groups of human subjects (n = 158): elderly nondemented control subjects; mild cognitive impairment (MCI) subjects with a clinical dementia rating (CDR) of 0.5; SAD subjects with CDR of 1.0; and other neurological disease (OND) control subjects. The CSF minor p3-Alcα variant, p3-Alcα38, was elevated (p <0.05) in MCI subjects or SAD subjects, depending upon whether the data were pooled and analyzed as a single cohort or analyzed individually as 3 separate cohorts. Interpretation: These results suggest that some SAD may involve alternative processing of multiple γ-secretase substrates, raising the possibility that the molecular pathogenesis of SAD might involve γ-secretase dysfunction.

Original languageEnglish (US)
Pages (from-to)1026-1031
Number of pages6
JournalAnnals of Neurology
Volume69
Issue number6
DOIs
StatePublished - Jun 2011

Fingerprint

Amyloid Precursor Protein Secretases
Alzheimer Disease
Presenilin-1
Cerebrospinal Fluid
Amyloid beta-Protein Precursor
Dementia
Mutation
Peptide Fragments
Conditioned Culture Medium
Cognitive Dysfunction
Immunoprecipitation
Amyloid
Population
Mass Spectrometry
Peptides
Genes

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Alternative processing of γ-secretase substrates in common forms of mild cognitive impairment and alzheimer's disease : Evidence for γ-secretase dysfunction. / Hata, Saori; Fujishige, Sayaka; Araki, Yoichi; Taniguchi, Miyako; Urakami, Katsuya; Peskind, Elaine; Akatsu, Hiroyasu; Araseki, Masahiko; Yamamoto, Kazuo; Martins, Ralph N.; Maeda, Masahiro; Nishimura, Masaki; Levey, Allan; Chung, Kathryn (Kathy); Montine, Thomas; Leverenz, James; Fagan, Anne; Goate, Alison; Bateman, Randall; Holtzman, David M.; Yamamoto, Tohru; Nakaya, Tadashi; Gandy, Sam; Suzuki, Toshiharu.

In: Annals of Neurology, Vol. 69, No. 6, 06.2011, p. 1026-1031.

Research output: Contribution to journalArticle

Hata, S, Fujishige, S, Araki, Y, Taniguchi, M, Urakami, K, Peskind, E, Akatsu, H, Araseki, M, Yamamoto, K, Martins, RN, Maeda, M, Nishimura, M, Levey, A, Chung, KK, Montine, T, Leverenz, J, Fagan, A, Goate, A, Bateman, R, Holtzman, DM, Yamamoto, T, Nakaya, T, Gandy, S & Suzuki, T 2011, 'Alternative processing of γ-secretase substrates in common forms of mild cognitive impairment and alzheimer's disease: Evidence for γ-secretase dysfunction', Annals of Neurology, vol. 69, no. 6, pp. 1026-1031. https://doi.org/10.1002/ana.22343
Hata, Saori ; Fujishige, Sayaka ; Araki, Yoichi ; Taniguchi, Miyako ; Urakami, Katsuya ; Peskind, Elaine ; Akatsu, Hiroyasu ; Araseki, Masahiko ; Yamamoto, Kazuo ; Martins, Ralph N. ; Maeda, Masahiro ; Nishimura, Masaki ; Levey, Allan ; Chung, Kathryn (Kathy) ; Montine, Thomas ; Leverenz, James ; Fagan, Anne ; Goate, Alison ; Bateman, Randall ; Holtzman, David M. ; Yamamoto, Tohru ; Nakaya, Tadashi ; Gandy, Sam ; Suzuki, Toshiharu. / Alternative processing of γ-secretase substrates in common forms of mild cognitive impairment and alzheimer's disease : Evidence for γ-secretase dysfunction. In: Annals of Neurology. 2011 ; Vol. 69, No. 6. pp. 1026-1031.
@article{6295038e28a54aab9d34051bb0098dbb,
title = "Alternative processing of γ-secretase substrates in common forms of mild cognitive impairment and alzheimer's disease: Evidence for γ-secretase dysfunction",
abstract = "Objective: The most common pathogenesis for familial Alzheimer's disease (FAD) involves misprocessing (or alternative processing) of the amyloid precursor protein (APP) by γ-secretase due to mutations of the presenilin 1 (PS1) gene. This misprocessing/alternative processing leads to an increase in the ratio of the level of a minor γ-secretase reaction product (Aβ42) to that of the major reaction product (Aβ40). Although no PS1 mutations are present, altered Aβ42/40 ratios are also observed in sporadic Alzheimer's disease (SAD), and these altered ratios apparently reflect deposition of Aβ42 as amyloid. Methods: Using immunoprecipitation-mass spectrometry with quantitative accuracy, we analyzed in the cerebrospinal fluid (CSF) of various clinical populations the peptide products generated by processing of not only APP but also an unrelated protein, alcadein (Alc). Alc undergoes metabolism by the identical APP α-secretases and γ-secretases, yielding a fragment that we have named p3-Alc α because of the parallel genesis of p3-Alcα peptides and the p3 fragment of APP. As with Aβ, both major and minor p3-Alcαs are generated. We studied the alternative processing of p3-Alcα in various clinical populations. Results: We previously reported that changes in the Aβ42/40 ratio showed covariance in a linear relationship with the levels of p3-Alcα [minor/major] ratio in media conditioned by cells expressing FAD-linked PS1 mutants. Here we studied the speciation of p3-Alcα in the CSF from 3 groups of human subjects (n = 158): elderly nondemented control subjects; mild cognitive impairment (MCI) subjects with a clinical dementia rating (CDR) of 0.5; SAD subjects with CDR of 1.0; and other neurological disease (OND) control subjects. The CSF minor p3-Alcα variant, p3-Alcα38, was elevated (p <0.05) in MCI subjects or SAD subjects, depending upon whether the data were pooled and analyzed as a single cohort or analyzed individually as 3 separate cohorts. Interpretation: These results suggest that some SAD may involve alternative processing of multiple γ-secretase substrates, raising the possibility that the molecular pathogenesis of SAD might involve γ-secretase dysfunction.",
author = "Saori Hata and Sayaka Fujishige and Yoichi Araki and Miyako Taniguchi and Katsuya Urakami and Elaine Peskind and Hiroyasu Akatsu and Masahiko Araseki and Kazuo Yamamoto and Martins, {Ralph N.} and Masahiro Maeda and Masaki Nishimura and Allan Levey and Chung, {Kathryn (Kathy)} and Thomas Montine and James Leverenz and Anne Fagan and Alison Goate and Randall Bateman and Holtzman, {David M.} and Tohru Yamamoto and Tadashi Nakaya and Sam Gandy and Toshiharu Suzuki",
year = "2011",
month = "6",
doi = "10.1002/ana.22343",
language = "English (US)",
volume = "69",
pages = "1026--1031",
journal = "Annals of Neurology",
issn = "0364-5134",
publisher = "John Wiley and Sons Inc.",
number = "6",

}

TY - JOUR

T1 - Alternative processing of γ-secretase substrates in common forms of mild cognitive impairment and alzheimer's disease

T2 - Evidence for γ-secretase dysfunction

AU - Hata, Saori

AU - Fujishige, Sayaka

AU - Araki, Yoichi

AU - Taniguchi, Miyako

AU - Urakami, Katsuya

AU - Peskind, Elaine

AU - Akatsu, Hiroyasu

AU - Araseki, Masahiko

AU - Yamamoto, Kazuo

AU - Martins, Ralph N.

AU - Maeda, Masahiro

AU - Nishimura, Masaki

AU - Levey, Allan

AU - Chung, Kathryn (Kathy)

AU - Montine, Thomas

AU - Leverenz, James

AU - Fagan, Anne

AU - Goate, Alison

AU - Bateman, Randall

AU - Holtzman, David M.

AU - Yamamoto, Tohru

AU - Nakaya, Tadashi

AU - Gandy, Sam

AU - Suzuki, Toshiharu

PY - 2011/6

Y1 - 2011/6

N2 - Objective: The most common pathogenesis for familial Alzheimer's disease (FAD) involves misprocessing (or alternative processing) of the amyloid precursor protein (APP) by γ-secretase due to mutations of the presenilin 1 (PS1) gene. This misprocessing/alternative processing leads to an increase in the ratio of the level of a minor γ-secretase reaction product (Aβ42) to that of the major reaction product (Aβ40). Although no PS1 mutations are present, altered Aβ42/40 ratios are also observed in sporadic Alzheimer's disease (SAD), and these altered ratios apparently reflect deposition of Aβ42 as amyloid. Methods: Using immunoprecipitation-mass spectrometry with quantitative accuracy, we analyzed in the cerebrospinal fluid (CSF) of various clinical populations the peptide products generated by processing of not only APP but also an unrelated protein, alcadein (Alc). Alc undergoes metabolism by the identical APP α-secretases and γ-secretases, yielding a fragment that we have named p3-Alc α because of the parallel genesis of p3-Alcα peptides and the p3 fragment of APP. As with Aβ, both major and minor p3-Alcαs are generated. We studied the alternative processing of p3-Alcα in various clinical populations. Results: We previously reported that changes in the Aβ42/40 ratio showed covariance in a linear relationship with the levels of p3-Alcα [minor/major] ratio in media conditioned by cells expressing FAD-linked PS1 mutants. Here we studied the speciation of p3-Alcα in the CSF from 3 groups of human subjects (n = 158): elderly nondemented control subjects; mild cognitive impairment (MCI) subjects with a clinical dementia rating (CDR) of 0.5; SAD subjects with CDR of 1.0; and other neurological disease (OND) control subjects. The CSF minor p3-Alcα variant, p3-Alcα38, was elevated (p <0.05) in MCI subjects or SAD subjects, depending upon whether the data were pooled and analyzed as a single cohort or analyzed individually as 3 separate cohorts. Interpretation: These results suggest that some SAD may involve alternative processing of multiple γ-secretase substrates, raising the possibility that the molecular pathogenesis of SAD might involve γ-secretase dysfunction.

AB - Objective: The most common pathogenesis for familial Alzheimer's disease (FAD) involves misprocessing (or alternative processing) of the amyloid precursor protein (APP) by γ-secretase due to mutations of the presenilin 1 (PS1) gene. This misprocessing/alternative processing leads to an increase in the ratio of the level of a minor γ-secretase reaction product (Aβ42) to that of the major reaction product (Aβ40). Although no PS1 mutations are present, altered Aβ42/40 ratios are also observed in sporadic Alzheimer's disease (SAD), and these altered ratios apparently reflect deposition of Aβ42 as amyloid. Methods: Using immunoprecipitation-mass spectrometry with quantitative accuracy, we analyzed in the cerebrospinal fluid (CSF) of various clinical populations the peptide products generated by processing of not only APP but also an unrelated protein, alcadein (Alc). Alc undergoes metabolism by the identical APP α-secretases and γ-secretases, yielding a fragment that we have named p3-Alc α because of the parallel genesis of p3-Alcα peptides and the p3 fragment of APP. As with Aβ, both major and minor p3-Alcαs are generated. We studied the alternative processing of p3-Alcα in various clinical populations. Results: We previously reported that changes in the Aβ42/40 ratio showed covariance in a linear relationship with the levels of p3-Alcα [minor/major] ratio in media conditioned by cells expressing FAD-linked PS1 mutants. Here we studied the speciation of p3-Alcα in the CSF from 3 groups of human subjects (n = 158): elderly nondemented control subjects; mild cognitive impairment (MCI) subjects with a clinical dementia rating (CDR) of 0.5; SAD subjects with CDR of 1.0; and other neurological disease (OND) control subjects. The CSF minor p3-Alcα variant, p3-Alcα38, was elevated (p <0.05) in MCI subjects or SAD subjects, depending upon whether the data were pooled and analyzed as a single cohort or analyzed individually as 3 separate cohorts. Interpretation: These results suggest that some SAD may involve alternative processing of multiple γ-secretase substrates, raising the possibility that the molecular pathogenesis of SAD might involve γ-secretase dysfunction.

UR - http://www.scopus.com/inward/record.url?scp=79959453985&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79959453985&partnerID=8YFLogxK

U2 - 10.1002/ana.22343

DO - 10.1002/ana.22343

M3 - Article

C2 - 21681798

AN - SCOPUS:79959453985

VL - 69

SP - 1026

EP - 1031

JO - Annals of Neurology

JF - Annals of Neurology

SN - 0364-5134

IS - 6

ER -