EXPRESSION OF AMYLOID PRECURSOR PROTEIN MESSENGER-RNA ISOFORMS IN RAT-BRAIN IS DIFFERENTIALLY REGULATED DURING POSTNATAL MATURATION AND BY CHOLINERGIC ACTIVITY

Pathological processing of the amyloid precursor protein (APP) is assu med to be responsible for the amyloid deposits in Alzheimer-diseased b rain tissue, but the physiological function of this protein in the bra in is still unclear. The aim of this study is to reveal whether the ex pression of different splicing variants of APP transcripts in distinct brain regions is driven by postnatal maturation and/or regulated by c ortical cholinergic transmission, applying quantitative in situ hybrid ization histochemistry using S-35-labeled oligonucleotides as specific probes to differentiate between APP isoforms. In cortical brain regio ns, the expression of both APP695 and APP751 is high at birth and exhi bits nearly adult levels. The developmental expression pattern of cort ical APP695 displays a peak value around postnatal day 10, while the a ge-related expression of APP751 demonstrates peak values on postnatal days 10 and 25, with the highest steady state levels of APP751 mRNA on day 25. During early development, the cortical laminar distribution o f the APP695, but not APP751, mRNA transiently changes from a more hom ogeneous distribution at birth to a pronounced laminar pattern with hi gher mRNA levels in cortical layer III/IV detectable at the age of 4 d ays and persisting until postnatal day 10. The distinct age-related ch anges in cortical APP695 and APP751 mRNA levels reflect the functional alterations during early brain maturation and suggest that APP695 mig ht play a role in establishing the mature connectional pattern between neurons, whereas APP751 could play a role in controlling cellular gro wth and synaptogenesis. Lesion of basal forebrain cholinergic system b y the selective cholinergic immunotoxin 192IgG-saporin resulted in dec reased levels of APP695 but not APP751 and APP770 transcripts by about 15-20% in some cortical (cingulate, frontal, parietal, piriform corte x), hippocampal regions (CAI, dentate gyrus), and basal forebrain nucl ei (medial septum, vertical Limb of diagonal band), detectable not ear lier than 30 days after lesion and persisting until 90 days postlesion , suggesting that the nearly complete loss of cortical cholinergic inp ut does not have any significant impact on the expression of APP mRNA isoforms in cholinoceptive cortical target regions. (C) 1997 ISDN.