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Increased monoamine oxidase messenger RNA expression levels in frontal cortex of Alzheimer's disease patients
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
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2002 (English)In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 326, no 1, 56-60. p.Article in journal (Refereed) Published
Abstract [en]

Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia in the industrialised world. The two monoamine oxidase (MAO) enzymes, monoamine oxidase A (MAOA) and monoamine oxidase B (MAOB), are important in the metabolism of monoamine neurotransmitters. AD and ageing have been shown to increase enzyme activity for both MAOA and MAOB. An increase (rather than decrease) of enzyme activity is a rare event in a disease that results in a decrease in the number of cells in the brain. The mechanism, transcriptional or post-transcriptional, responsible for the increase in protein activity, is not known. In this study, we investigate for the first time the messenger RNA (mRNA) expression levels of both MAOA and MAOB in 246 cortical brain samples obtained at autopsy from 62 AD patients and 61 normal controls. We found a significant increase in mRNA levels for both MAOA (P=0.001) and MAOB (P=0.002) in disease brain tissue. This indicates that both MAO enzymes might be important in the progression of AD.

Place, publisher, year, edition, pages
2002. Vol. 326, no 1, 56-60. p.
National Category
Genetics
Identifiers
URN: urn:nbn:se:uu:diva-93406DOI: 0.1016/S0304-3940(02)00307-5OAI: oai:DiVA.org:uu-93406DiVA: diva2:166870
Available from: 2005-09-08 Created: 2005-09-08 Last updated: 2017-12-14Bibliographically 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

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