REGIONAL DISTRIBUTION OF THE ALTERNATIVELY SPLICED ISOFORMS OF BETA-APP RNA TRANSCRIPT IN THE BRAIN OF NORMAL, HETEROZYGOUS AND HOMOZYGOUS WEAVER MUTANT MICE AS REVEALED BY INSITU HYBRIDIZATION HISTOCHEMISTRY

The cellular localization of amyloid beta-protein precursor (betaAPP) RNA transcripts was studied by in situ hybridization histochemistry in normal, heterozygous and homozygous weaver (wv) mutant mice, which lose midbrain dopamine (DA) neurons, cerebellar granule cells, and Purkinje cells. The betaAPP gene is located at the distal end of mouse chromosome (MMU) 16, on which the wv locus has been assigned as well. Transcripts encoding isoforms betaAPP695, betaAPP714 and betaAPP751 were present in several different brain areas of normal (+ / +) mice, including hippocampus, substantia nigra (SN) pars compacta and cerebellum. The same transcripts were progressively reduced in homozygous weaver (wu / wv) SN, in correlation with DA neuron loss. The betaAPP770 species - normally seen in striatum and not SN - was present in the mutant striatum. There were not any obvious changes in betaAPP expression in the nigrostriatal system of weaver heterozygotes (wv / +). In normal cerebellum, Purkinje cells showed very high levels of hybridization signal for betaAPP695, betaAPP714 and betaAPP751 RNA transcripts, and a moderate signal for the betaAPP770 species. In weaver heterozygotes and homozygotes, Purkinje cells, which are typically not arranged in a monolayer, showed strong hybridization signal. No changes in betaAPP mRNAs were observed in brain areas other than the cerebellum and ventral midbrain of weaver mutants. These findings suggest that the decreased betaAPP gene expression seen in the cerebellum and SN of weaver mutants most likely represents an epiphenomenon of the regional nerve cell loss and, therefore, the wv gene defect on MMU 16 does not seem to influence the expression of the closely linked betaAPP gene in brain areas outside the nigrostriatal pathway and cerebellar cortex.