Amyloid precursor protein mRNA levels in Alzheimer's disease brain.
Insoluble beta-amyloid deposits in Alzheimer's disease (AD) brain are proteolytically derived from the membrane bound amyloid precursor protein (APP). The APP gene is differentially spliced to produce isoforms that can be classified into those containing a Kunitz-type serine protease inhibitor domain (K(+), APP(751), APP(770), APRP(365) and APRP(563)), and those without (K(-), APP(695) and APP(714)). Given the hypothesis that Abeta is a result of aberrant catabolism of APP, differential expression of mRNA isoforms containing protease inhibitors might play an active role in the pathology of AD. We took 513 cerebral cortex samples from 90 AD and 81 control brains and quantified the mRNA isoforms of APP with TaqMan real-time RT-PCR. After adjustment for age at death, brain pH and gender we found a change in the ratio of KPI(+) to KPI(-) mRNA isoforms of APP. Three separate probes, designed to recognise only KPI(+) mRNA species, gave increases of between 28% and 50% in AD brains relative to controls (p=0.002). There was no change in the mRNA levels of KPI-(APP 695) (p=0.898). Therefore, whilst KPI-mRNA levels remained stable the KPI(+) species increased specifically in the AD brains.
Preece
Paul
P
Seixo Branco, Departamento de Neurologia, Rua das Brañas 7-bajo-D, Mera, 15177 Oleiros, La Coruña, Galicia, Spain. pablo@quantuum.com
Virley
David J
DJ
Costandi
Moheb
M
Coombes
Robert
R
Moss
Stephen J
SJ
Mudge
Anne W
AW
Jazin
Elena
E
Cairns
Nigel J
NJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D000704:Analysis of Variance; D016022:Case-Control Studies; D002540:Cerebral Cortex / Q000378:metabolism*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis / Q000235:genetics; D006801:Humans; D016014:Linear Models; D008297:Male; D008869:Microtubule-Associated Proteins / Q000032:analysis / Q000235:genetics; D008875:Middle Aged; D020033:Protein Isoforms / Q000032:analysis / Q000145:classification / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012737:Sex Factors
D016564:Amyloid beta-Protein Precursor; D005904:Glial Fibrillary Acidic Protein; D008869:Microtubule-Associated Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger