uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Alzheimer’s disease: mRNA expression profiles of multiple patients show alterations of genes involved with calcium signalling
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Animal Development and Genetics. (beteende genetik)
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Animal Development and Genetics. (beteende genetik)
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Animal Development and Genetics. (beteende genetik)
2006 (English)In: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 21, no 3, 618-625 p.Article in journal (Refereed) Published
Abstract [en]

We combined global and high-resolution strategies to find genes with altered mRNA expression levels in one of the largest collection of brain autopsies from Alzheimer's patients and controls ever studied. Our global analysis involved microarray hybridizations of large pools of samples obtained from 114 individuals, using two independent sets of microarrays. Ten genes selected from the microarray experiments were quantified on each individual separately using real-time RT-PCR. This high-resolution analysis accounted for systematic differences in age, postmortem interval, brain pH, and reference gene expression, and it estimated the effect of disease on mRNA levels, on top of the effect of all other variables. Differential expression was confirmed for eight out of ten genes. Among them, Type B inositol 1,4,5-trisphosphate 3-kinase (ITPKB), and regulator of G protein signaling 4 (RGS4) showed highly altered expression levels in patients (P values < 0.0001). Our results point towards increased inositol triphospate (IP3)-mediated calcium signaling in Alzheimer's disease.

Place, publisher, year, edition, pages
2006. Vol. 21, no 3, 618-625 p.
Keyword [en]
Aged, Aged; 80 and over, Alzheimer Disease/*genetics, Calcium Signaling/*genetics, Female, Gene Expression, Gene Expression Profiling, Humans, In Situ Hybridization, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, RNA; Messenger/analysis, Reverse Transcriptase Polymerase Chain Reaction
National Category
Genetics
Identifiers
URN: urn:nbn:se:uu:diva-93407DOI: 10.1016/j.nbd.2005.09.004PubMedID: 16257224OAI: oai:DiVA.org:uu-93407DiVA: diva2:166871
Available from: 2005-09-08 Created: 2005-09-08 Last updated: 2010-03-29Bibliographically approved
In thesis
1. Detection of Differentially Expressed Genes in Alzheimer's Disease: Regulator of G-protein Signalling 4: A Novel Mediator of APP Processing
Open this publication in new window or tab >>Detection of Differentially Expressed Genes in Alzheimer's Disease: Regulator of G-protein Signalling 4: A Novel Mediator of APP Processing
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Alzheimer’s disease is a neurodegenerative disease characterised by progressive memory deterioration and cognitive impairment. Pathological hallmarks are extracellular senile plaques, neurofibrillary tangles and neuron loss. Senile plaques are produced through altered processing of the membrane-bound protein APP. Different neurotransmitter signal transduction pathways have been implicated in the formation or development of Alzheimer’s pathologies, but the molecular mechanisms behind these changes are not well known.

The overall aims of this thesis were to identify novel genes with differential expression in Alzheimer’s disease and to investigate mechanisms initiating these changes and their relationship to the disease. A real-time RT-PCR strategy was developed to enable detection of small mRNA changes in human brain autopsy samples. This approach was first used to investigate levels of expression of a candidate gene (MAO), and later employed to verify gene expression differences detected by cDNA microarray analysis. Of several genes verified as differentially expressed in the patients, ITPKB (Inositol 1,4,5-trisphosphate 3-kinase B) and RGS4 (Regulator of G-protein signalling 4) presented the largest expression differences in Alzheimer’s cases compared to control samples. Several splice variants of RGS4 showed similar down-regulation levels and one rare haplotype was associated with decreased RGS4 expression. Functional studies in SH-SY5Y cell cultures overexpressing RGS4 showed that it is likely that RGS4 affects APP processing by regulating PRKC expression levels.

The combined expression of RGS4 and ITPKB is for the first time presented in this thesis as genes with altered mRNA levels in Alzheimer’s disease. These two genes are implicated in the same signalling pathway that modifies calcium levels in the cell. Furthermore, the fact that RGS4 affects APP processing suggests that RGS4 is involved in the development of senile plaques. This motivates further functional studies of this gene and suggests that RGS4 may become a new potential drug target for Alzheimer’s disease.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 52 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 85
Keyword
Alzheimer's disease, RGS4, ITPKB, RAB3A, APP processinig
National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-5910 (URN)91-554-6234-X (ISBN)
Public defence
2005-09-29, Ekman-salen, Norby vägen, EBC, 09:15 (English)
Opponent
Supervisors
Available from: 2005-09-08 Created: 2005-09-08 Last updated: 2010-02-08Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Authority records BETA

Jazin, Elena

Search in DiVA

By author/editor
Jazin, Elena
By organisation
Animal Development and Genetics
In the same journal
Neurobiology of Disease
Genetics

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 720 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf