Alzheimer-associated C allele of the promoter polymorphism -22C>T causes a critical neuron-specific decrease of presenilin 1 expression

44Citations
Citations of this article
26Readers
Mendeley users who have this article in their library.

This article is free to access.

Abstract

We, amongst others, have shown that CC homozygosity at the -22C>T promoter polymorphism in presenilin 1 (PSEN1) is associated with increased risk for Alzheimer's disease (AD). Also, studies in AD brains suggested that CC homozygosity increased the risk for AD by increasing the Aβ load. We characterized the PSEN1 promoter by deletion mapping, and analysed the effect of the -22C and -22T alleles on the transcriptional activity of PSEN1 in a transient transfection system. We showed a neuron-specific 2-fold decrease in promoter activity for the -22C risk allele, which in homozygous individuals would lead to a critical decrease in PSEN1 expression. The deletion mapping suggested that the 13 bp region (-33/-20) spanning the -22C>T polymorphism harbours a binding site for a negative regulatory factor. This factor has a higher affinity for the -22C risk allele and is strongly dependent on downstream sequences for cell-type-specific expression differences. Together, these studies provide evidence that the increased risk for AD associated with PSEN1 may result from genetic variations in the regulatory region, leading to altered expression levels of PSEN1 in neurons.

References Powered by Scopus

Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei

10361Citations
N/AReaders
Get full text

Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease

4047Citations
N/AReaders
Get full text

Matlnd and matlnspector: New fast and versatile tools for detection of consensus matches in nucleotide sequence data

2441Citations
N/AReaders
Get full text

Cited by Powered by Scopus

Schizophrenia genes, gene expression, and neuropathology: On the matter of their convergence

1745Citations
N/AReaders
Get full text

Twenty years of the Alzheimer's disease amyloid hypothesis: A genetic perspective

1623Citations
N/AReaders
Get full text

Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration

668Citations
N/AReaders
Get full text

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Cite

CITATION STYLE

APA

Theuns, J., Remacle, J., Killick, R., Corsmit, E., Vennekens, K., Huylebroeck, D., … Van Broeckhoven, C. (2003). Alzheimer-associated C allele of the promoter polymorphism -22C>T causes a critical neuron-specific decrease of presenilin 1 expression. Human Molecular Genetics, 12(8), 869–877. https://doi.org/10.1093/hmg/ddg098

Readers' Seniority

Tooltip

PhD / Post grad / Masters / Doc 8

62%

Professor / Associate Prof. 3

23%

Lecturer / Post doc 1

8%

Researcher 1

8%

Readers' Discipline

Tooltip

Medicine and Dentistry 5

31%

Neuroscience 4

25%

Agricultural and Biological Sciences 4

25%

Social Sciences 3

19%

Save time finding and organizing research with Mendeley

Sign up for free