beta-site APP cleaving enzyme mRNA expression in APP transgenic mice: anatomical overlap with transgene expression and static levels with aging.

The principal enzyme responsible for the beta-site cleavage of amyloid precursor protein (APP) in the brain is a membrane-bound aspartyl protease beta-site APP cleaving enzyme (BACE). We examined human APP (hAPP) and BACE mRNA expression by in situ hybridization in young and old hAPP transgenic mice from two lines: Tg2576, hAPP KM670-671NL (hAPP(Sw)) at 4 and 15 months; and PDAPP, hAPP V717F, at 4 and 11 months. In transgene-positive mice from both lines, hAPP expression was most prominent in cortical, cerebellar, and hippocampal neuronal populations. Cingulate, entorhinal, and hippocampal amyloid burden in transgene-positive 16-month Tg2576 mice was 4 to 8%, and in 12-month PDAPP mice, 2 to 4%; there was no cerebellar amyloid deposition. BACE expression in transgenic and nontransgenic mice was highest in the cerebellar granule cell layer and hippocampal neuronal layers, intermediate in cortex, lower in subcortical regions, and minimal or absent in white matter of the cerebellum. Emulsion-dipped sections confirmed a predominantly neuronal pattern of expression. The amount of hybridization signal did not differ between transgenic and nontransgenic mice, or young and old mice, within each line. Thus, hAPP and endogenous BACE expression in similar anatomical localizations allow for processing of hAPP and Abeta formation in hAPP transgenic mice, but these are modified by additional age-related and anatomical factors.