Familial Alzheimer's disease-linked presenilin I variants elevate aβ1- 42/1-40 ratio in vitro and in vivo

David R. Borchelt, Gopal Thinakaran, Christopher B. Eckman, Michael K. Lee, Frances Davenport, Tamara Ratovitsky, Cristian Mihail Prada, Grace Kim, Sophia Seekins, Debra Yager, Hilda H. Slunt, Rong Wang, Mary Seeger, Allan I. Levey, Samuel E. Gandy, Neal G. Copeland, Nancy A. Jenkins, Donald L. Price, Steven G. Younkin, Sangram S. Sisodia

Research output: Contribution to journalArticle

Abstract

Mutations in the presenilin 1 (PS1) and presenilin 2 genes cosegregate with the majority of early-onset familial Alzheimer's disease (FAD) pedigrees. We now document that the Aβ1-42(43)/Aβ1-40 ratio in the conditioned media of independent N2a cell lines expressing three FAD-linked PS1 variants is uniformly elevated relative to cells expressing similar levels of wild-type PS1. Similarly, the Aβ 1-42(43)/Aβ1-40 ratio is elevated in the brains of young transgenic animals coexpressing a chimeric amyloid precursor protein (APP) and an FAD-linked PS1 variant compared with brains of transgenic mice expressing APP alone or transgenic mice coexpressing wild-type human PS1 and APP. These studies provide compelling support for the view that one mechanism by which these mutant PS1 cause AD is by increasing the extracellular concentration of Aβ peptides terminating at 42(43), species that foster Aβ deposition.

Original languageEnglish (US)
Pages (from-to)1005-1013
Number of pages9
JournalNeuron
Volume17
Issue number5
DOIs
StatePublished - Nov 1996

Fingerprint

Presenilins
Presenilin-1
Alzheimer Disease
Amyloid beta-Protein Precursor
Transgenic Mice
Presenilin-2
Genetically Modified Animals
Brain
Pedigree
Conditioned Culture Medium
In Vitro Techniques
Cell Line
Peptides
Mutation
Genes

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Borchelt, D. R., Thinakaran, G., Eckman, C. B., Lee, M. K., Davenport, F., Ratovitsky, T., ... Sisodia, S. S. (1996). Familial Alzheimer's disease-linked presenilin I variants elevate aβ1- 42/1-40 ratio in vitro and in vivo. Neuron, 17(5), 1005-1013. https://doi.org/10.1016/S0896-6273(00)80230-5

Familial Alzheimer's disease-linked presenilin I variants elevate aβ1- 42/1-40 ratio in vitro and in vivo. / Borchelt, David R.; Thinakaran, Gopal; Eckman, Christopher B.; Lee, Michael K.; Davenport, Frances; Ratovitsky, Tamara; Prada, Cristian Mihail; Kim, Grace; Seekins, Sophia; Yager, Debra; Slunt, Hilda H.; Wang, Rong; Seeger, Mary; Levey, Allan I.; Gandy, Samuel E.; Copeland, Neal G.; Jenkins, Nancy A.; Price, Donald L.; Younkin, Steven G.; Sisodia, Sangram S.

In: Neuron, Vol. 17, No. 5, 11.1996, p. 1005-1013.

Research output: Contribution to journalArticle

Borchelt, DR, Thinakaran, G, Eckman, CB, Lee, MK, Davenport, F, Ratovitsky, T, Prada, CM, Kim, G, Seekins, S, Yager, D, Slunt, HH, Wang, R, Seeger, M, Levey, AI, Gandy, SE, Copeland, NG, Jenkins, NA, Price, DL, Younkin, SG & Sisodia, SS 1996, 'Familial Alzheimer's disease-linked presenilin I variants elevate aβ1- 42/1-40 ratio in vitro and in vivo', Neuron, vol. 17, no. 5, pp. 1005-1013. https://doi.org/10.1016/S0896-6273(00)80230-5
Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T et al. Familial Alzheimer's disease-linked presenilin I variants elevate aβ1- 42/1-40 ratio in vitro and in vivo. Neuron. 1996 Nov;17(5):1005-1013. https://doi.org/10.1016/S0896-6273(00)80230-5
Borchelt, David R. ; Thinakaran, Gopal ; Eckman, Christopher B. ; Lee, Michael K. ; Davenport, Frances ; Ratovitsky, Tamara ; Prada, Cristian Mihail ; Kim, Grace ; Seekins, Sophia ; Yager, Debra ; Slunt, Hilda H. ; Wang, Rong ; Seeger, Mary ; Levey, Allan I. ; Gandy, Samuel E. ; Copeland, Neal G. ; Jenkins, Nancy A. ; Price, Donald L. ; Younkin, Steven G. ; Sisodia, Sangram S. / Familial Alzheimer's disease-linked presenilin I variants elevate aβ1- 42/1-40 ratio in vitro and in vivo. In: Neuron. 1996 ; Vol. 17, No. 5. pp. 1005-1013.
@article{efc9096cf9174a3aa65ebc8b3fba91f9,
title = "Familial Alzheimer's disease-linked presenilin I variants elevate aβ1- 42/1-40 ratio in vitro and in vivo",
abstract = "Mutations in the presenilin 1 (PS1) and presenilin 2 genes cosegregate with the majority of early-onset familial Alzheimer's disease (FAD) pedigrees. We now document that the Aβ1-42(43)/Aβ1-40 ratio in the conditioned media of independent N2a cell lines expressing three FAD-linked PS1 variants is uniformly elevated relative to cells expressing similar levels of wild-type PS1. Similarly, the Aβ 1-42(43)/Aβ1-40 ratio is elevated in the brains of young transgenic animals coexpressing a chimeric amyloid precursor protein (APP) and an FAD-linked PS1 variant compared with brains of transgenic mice expressing APP alone or transgenic mice coexpressing wild-type human PS1 and APP. These studies provide compelling support for the view that one mechanism by which these mutant PS1 cause AD is by increasing the extracellular concentration of Aβ peptides terminating at 42(43), species that foster Aβ deposition.",
author = "Borchelt, {David R.} and Gopal Thinakaran and Eckman, {Christopher B.} and Lee, {Michael K.} and Frances Davenport and Tamara Ratovitsky and Prada, {Cristian Mihail} and Grace Kim and Sophia Seekins and Debra Yager and Slunt, {Hilda H.} and Rong Wang and Mary Seeger and Levey, {Allan I.} and Gandy, {Samuel E.} and Copeland, {Neal G.} and Jenkins, {Nancy A.} and Price, {Donald L.} and Younkin, {Steven G.} and Sisodia, {Sangram S.}",
year = "1996",
month = "11",
doi = "10.1016/S0896-6273(00)80230-5",
language = "English (US)",
volume = "17",
pages = "1005--1013",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "5",

}

TY - JOUR

T1 - Familial Alzheimer's disease-linked presenilin I variants elevate aβ1- 42/1-40 ratio in vitro and in vivo

AU - Borchelt, David R.

AU - Thinakaran, Gopal

AU - Eckman, Christopher B.

AU - Lee, Michael K.

AU - Davenport, Frances

AU - Ratovitsky, Tamara

AU - Prada, Cristian Mihail

AU - Kim, Grace

AU - Seekins, Sophia

AU - Yager, Debra

AU - Slunt, Hilda H.

AU - Wang, Rong

AU - Seeger, Mary

AU - Levey, Allan I.

AU - Gandy, Samuel E.

AU - Copeland, Neal G.

AU - Jenkins, Nancy A.

AU - Price, Donald L.

AU - Younkin, Steven G.

AU - Sisodia, Sangram S.

PY - 1996/11

Y1 - 1996/11

N2 - Mutations in the presenilin 1 (PS1) and presenilin 2 genes cosegregate with the majority of early-onset familial Alzheimer's disease (FAD) pedigrees. We now document that the Aβ1-42(43)/Aβ1-40 ratio in the conditioned media of independent N2a cell lines expressing three FAD-linked PS1 variants is uniformly elevated relative to cells expressing similar levels of wild-type PS1. Similarly, the Aβ 1-42(43)/Aβ1-40 ratio is elevated in the brains of young transgenic animals coexpressing a chimeric amyloid precursor protein (APP) and an FAD-linked PS1 variant compared with brains of transgenic mice expressing APP alone or transgenic mice coexpressing wild-type human PS1 and APP. These studies provide compelling support for the view that one mechanism by which these mutant PS1 cause AD is by increasing the extracellular concentration of Aβ peptides terminating at 42(43), species that foster Aβ deposition.

AB - Mutations in the presenilin 1 (PS1) and presenilin 2 genes cosegregate with the majority of early-onset familial Alzheimer's disease (FAD) pedigrees. We now document that the Aβ1-42(43)/Aβ1-40 ratio in the conditioned media of independent N2a cell lines expressing three FAD-linked PS1 variants is uniformly elevated relative to cells expressing similar levels of wild-type PS1. Similarly, the Aβ 1-42(43)/Aβ1-40 ratio is elevated in the brains of young transgenic animals coexpressing a chimeric amyloid precursor protein (APP) and an FAD-linked PS1 variant compared with brains of transgenic mice expressing APP alone or transgenic mice coexpressing wild-type human PS1 and APP. These studies provide compelling support for the view that one mechanism by which these mutant PS1 cause AD is by increasing the extracellular concentration of Aβ peptides terminating at 42(43), species that foster Aβ deposition.

UR - http://www.scopus.com/inward/record.url?scp=0030293676&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030293676&partnerID=8YFLogxK

U2 - 10.1016/S0896-6273(00)80230-5

DO - 10.1016/S0896-6273(00)80230-5

M3 - Article

C2 - 8938131

AN - SCOPUS:0030293676

VL - 17

SP - 1005

EP - 1013

JO - Neuron

JF - Neuron

SN - 0896-6273

IS - 5

ER -