Allele-specific overexpression in astrocytes of an Alzheimer's disease associated alpha-1-antichymotrypsin promoter polymorphism.
Alpha-1-antichymotrypsin (ACT), a serine proteinase inhibitor is synthesised predominantly in the liver and in other tissues including the brain. ACT is a major component of the senile plaques (SP) characteristic of Alzheimer's disease (AD). Increased production locally in the brain may be associated with Alzheimer's disease as ACT acts as a "pathological chaperone", promoting beta-amyloid assembly into neurotoxic fibrils. Recent reports suggest that the T allele of a G/T polymorphism at position -51 of ACT is associated with cognitive decline in AD patients. We demonstrate that the T allele is markedly overexpressed by almost 225% in an astrocytic cell line in response to oncostatin M (OSM) compared with a 35% increase in a mixed population of brain-derived cells. This effect is probably mediated by a higher binding affinity of the transcription initiation complex to the higher expressing allele and overexpression of ACT by astrocytes could thus contribute to increased beta-amyloid fibril formation in AD.
Ritchie
Alistair
A
Division of Clinical Chemistry, Institute of Genetics, Queens' Medical Centre, University of Nottingham, Nottingham, NG7 2UH, UK.
Morgan
Kevin
K
Kalsheker
Noor
N
D000483:Alleles; D000544:Alzheimer Disease / Q000503:physiopathology*; D001253:Astrocytes / Q000166:cytology / Q000502:physiology*; D001483:Base Sequence; D002460:Cell Line; D024202:Electrophoretic Mobility Shift Assay; D015870:Gene Expression; D006801:Humans; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D000514:alpha 1-Antichymotrypsin / Q000235:genetics* / Q000378:metabolism
D000514:alpha 1-Antichymotrypsin