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Familial Alzheimer's disease-associated presenilin-1 alters cerebellar activity and calcium homeostasis

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Familial Alzheimer's disease-associated presenilin-1 alters cerebellar activity and calcium homeostasis. / Sepulveda-Falla, Diego; Barrera-Ocampo, Alvaro A; Hagel, Christian; Korwitz, Anne; Vinueza-Veloz, Maria Fernanda; Zhou, Kuikui; Schonewille, Martijn; Zhou, Haibo; Velazquez-Perez, Luis; Rodriguez-Labrada, Roberto; Villegas, Andres; Ferrer, Isidro; Lopera, Francisco; Langer, Thomas; De Zeeuw, Chris I; Glatzel, Markus.

In: J CLIN INVEST, Vol. 124, No. 4, 01.04.2014, p. 1552-67.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Sepulveda-Falla, D, Barrera-Ocampo, AA, Hagel, C, Korwitz, A, Vinueza-Veloz, MF, Zhou, K, Schonewille, M, Zhou, H, Velazquez-Perez, L, Rodriguez-Labrada, R, Villegas, A, Ferrer, I, Lopera, F, Langer, T, De Zeeuw, CI & Glatzel, M 2014, 'Familial Alzheimer's disease-associated presenilin-1 alters cerebellar activity and calcium homeostasis', J CLIN INVEST, vol. 124, no. 4, pp. 1552-67. https://doi.org/10.1172/JCI66407

APA

Sepulveda-Falla, D., Barrera-Ocampo, A. A., Hagel, C., Korwitz, A., Vinueza-Veloz, M. F., Zhou, K., Schonewille, M., Zhou, H., Velazquez-Perez, L., Rodriguez-Labrada, R., Villegas, A., Ferrer, I., Lopera, F., Langer, T., De Zeeuw, C. I., & Glatzel, M. (2014). Familial Alzheimer's disease-associated presenilin-1 alters cerebellar activity and calcium homeostasis. J CLIN INVEST, 124(4), 1552-67. https://doi.org/10.1172/JCI66407

Vancouver

Sepulveda-Falla D, Barrera-Ocampo AA, Hagel C, Korwitz A, Vinueza-Veloz MF, Zhou K et al. Familial Alzheimer's disease-associated presenilin-1 alters cerebellar activity and calcium homeostasis. J CLIN INVEST. 2014 Apr 1;124(4):1552-67. https://doi.org/10.1172/JCI66407

Bibtex

@article{33711375fafc45d9a27379a1ba13c991,
title = "Familial Alzheimer's disease-associated presenilin-1 alters cerebellar activity and calcium homeostasis",
abstract = "Familial Alzheimer's disease (FAD) is characterized by autosomal dominant heritability and early disease onset. Mutations in the gene encoding presenilin-1 (PS1) are found in approximately 80% of cases of FAD, with some of these patients presenting cerebellar damage with amyloid plaques and ataxia with unclear pathophysiology. A Colombian kindred carrying the PS1-E280A mutation is the largest known cohort of PS1-FAD patients. Here, we investigated PS1-E280A-associated cerebellar dysfunction and found that it occurs early in PS1-E208A carriers, while cerebellar signs are highly prevalent in patients with dementia. Postmortem analysis of cerebella of PS1-E280A carrier revealed greater Purkinje cell (PC) loss and more abnormal mitochondria compared with controls. In PS1-E280A tissue, ER/mitochondria tethering was impaired, Ca2+ channels IP3Rs and CACNA1A were downregulated, and Ca2+-dependent mitochondrial transport proteins MIRO1 and KIF5C were reduced. Accordingly, expression of PS1-E280A in a neuronal cell line altered ER/mitochondria tethering and transport compared with that in cells expressing wild-type PS1. In a murine model of PS1-FAD, animals exhibited mild ataxia and reduced PC simple spike activity prior to cerebellar β-amyloid deposition. Our data suggest that impaired calcium homeostasis and mitochondrial dysfunction in PS1-FAD PCs reduces their activity and contributes to motor coordination deficits prior to Aβ aggregation and dementia. We propose that PS1-E280A affects both Ca2+ homeostasis and Aβ precursor processing, leading to FAD and neurodegeneration.",
keywords = "Adult, Aged, Aged, 80 and over, Alzheimer Disease, Amino Acid Substitution, Amyloid beta-Protein Precursor, Animals, Calcium, Case-Control Studies, Cell Line, Cerebellum, Disease Models, Animal, Endoplasmic Reticulum, Female, Genes, Dominant, Heterozygote, Homeostasis, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Mice, Transgenic, Middle Aged, Mitochondria, Models, Neurological, Mutation, Missense, Presenilin-1, Purkinje Cells",
author = "Diego Sepulveda-Falla and Barrera-Ocampo, {Alvaro A} and Christian Hagel and Anne Korwitz and Vinueza-Veloz, {Maria Fernanda} and Kuikui Zhou and Martijn Schonewille and Haibo Zhou and Luis Velazquez-Perez and Roberto Rodriguez-Labrada and Andres Villegas and Isidro Ferrer and Francisco Lopera and Thomas Langer and {De Zeeuw}, {Chris I} and Markus Glatzel",
year = "2014",
month = apr,
day = "1",
doi = "10.1172/JCI66407",
language = "English",
volume = "124",
pages = "1552--67",
journal = "J CLIN INVEST",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "4",

}

RIS

TY - JOUR

T1 - Familial Alzheimer's disease-associated presenilin-1 alters cerebellar activity and calcium homeostasis

AU - Sepulveda-Falla, Diego

AU - Barrera-Ocampo, Alvaro A

AU - Hagel, Christian

AU - Korwitz, Anne

AU - Vinueza-Veloz, Maria Fernanda

AU - Zhou, Kuikui

AU - Schonewille, Martijn

AU - Zhou, Haibo

AU - Velazquez-Perez, Luis

AU - Rodriguez-Labrada, Roberto

AU - Villegas, Andres

AU - Ferrer, Isidro

AU - Lopera, Francisco

AU - Langer, Thomas

AU - De Zeeuw, Chris I

AU - Glatzel, Markus

PY - 2014/4/1

Y1 - 2014/4/1

N2 - Familial Alzheimer's disease (FAD) is characterized by autosomal dominant heritability and early disease onset. Mutations in the gene encoding presenilin-1 (PS1) are found in approximately 80% of cases of FAD, with some of these patients presenting cerebellar damage with amyloid plaques and ataxia with unclear pathophysiology. A Colombian kindred carrying the PS1-E280A mutation is the largest known cohort of PS1-FAD patients. Here, we investigated PS1-E280A-associated cerebellar dysfunction and found that it occurs early in PS1-E208A carriers, while cerebellar signs are highly prevalent in patients with dementia. Postmortem analysis of cerebella of PS1-E280A carrier revealed greater Purkinje cell (PC) loss and more abnormal mitochondria compared with controls. In PS1-E280A tissue, ER/mitochondria tethering was impaired, Ca2+ channels IP3Rs and CACNA1A were downregulated, and Ca2+-dependent mitochondrial transport proteins MIRO1 and KIF5C were reduced. Accordingly, expression of PS1-E280A in a neuronal cell line altered ER/mitochondria tethering and transport compared with that in cells expressing wild-type PS1. In a murine model of PS1-FAD, animals exhibited mild ataxia and reduced PC simple spike activity prior to cerebellar β-amyloid deposition. Our data suggest that impaired calcium homeostasis and mitochondrial dysfunction in PS1-FAD PCs reduces their activity and contributes to motor coordination deficits prior to Aβ aggregation and dementia. We propose that PS1-E280A affects both Ca2+ homeostasis and Aβ precursor processing, leading to FAD and neurodegeneration.

AB - Familial Alzheimer's disease (FAD) is characterized by autosomal dominant heritability and early disease onset. Mutations in the gene encoding presenilin-1 (PS1) are found in approximately 80% of cases of FAD, with some of these patients presenting cerebellar damage with amyloid plaques and ataxia with unclear pathophysiology. A Colombian kindred carrying the PS1-E280A mutation is the largest known cohort of PS1-FAD patients. Here, we investigated PS1-E280A-associated cerebellar dysfunction and found that it occurs early in PS1-E208A carriers, while cerebellar signs are highly prevalent in patients with dementia. Postmortem analysis of cerebella of PS1-E280A carrier revealed greater Purkinje cell (PC) loss and more abnormal mitochondria compared with controls. In PS1-E280A tissue, ER/mitochondria tethering was impaired, Ca2+ channels IP3Rs and CACNA1A were downregulated, and Ca2+-dependent mitochondrial transport proteins MIRO1 and KIF5C were reduced. Accordingly, expression of PS1-E280A in a neuronal cell line altered ER/mitochondria tethering and transport compared with that in cells expressing wild-type PS1. In a murine model of PS1-FAD, animals exhibited mild ataxia and reduced PC simple spike activity prior to cerebellar β-amyloid deposition. Our data suggest that impaired calcium homeostasis and mitochondrial dysfunction in PS1-FAD PCs reduces their activity and contributes to motor coordination deficits prior to Aβ aggregation and dementia. We propose that PS1-E280A affects both Ca2+ homeostasis and Aβ precursor processing, leading to FAD and neurodegeneration.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Alzheimer Disease

KW - Amino Acid Substitution

KW - Amyloid beta-Protein Precursor

KW - Animals

KW - Calcium

KW - Case-Control Studies

KW - Cell Line

KW - Cerebellum

KW - Disease Models, Animal

KW - Endoplasmic Reticulum

KW - Female

KW - Genes, Dominant

KW - Heterozygote

KW - Homeostasis

KW - Humans

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Mutant Strains

KW - Mice, Transgenic

KW - Middle Aged

KW - Mitochondria

KW - Models, Neurological

KW - Mutation, Missense

KW - Presenilin-1

KW - Purkinje Cells

U2 - 10.1172/JCI66407

DO - 10.1172/JCI66407

M3 - SCORING: Journal article

C2 - 24569455

VL - 124

SP - 1552

EP - 1567

JO - J CLIN INVEST

JF - J CLIN INVEST

SN - 0021-9738

IS - 4

ER -