beta-site APP cleaving enzyme mRNA expression in APP transgenic mice: anatomical overlap with transgene expression
M C Irizarry1, J J Locascio, B T Hyman
1Alzheimer Disease Research Unit, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Abstract:
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.
Insights
This study investigated amyloid precursor protein (APP) and beta-site APP cleaving enzyme (BACE) expression in transgenic mouse models. Findings show APP and BACE are expressed in similar brain regions, facilitating amyloid-beta formation, but influenced by age and anatomy.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Beta-site APP cleaving enzyme (BACE) is key for amyloid precursor protein (APP) cleavage in the brain.
- Understanding APP and BACE expression is crucial for Alzheimer's disease research.
Purpose of the Study:
- To examine human APP (hAPP) and BACE mRNA expression in young and old hAPP transgenic mice.
- To correlate gene expression patterns with amyloid deposition in different brain regions.
Main Methods:
- In situ hybridization was used to analyze hAPP and BACE mRNA expression in Tg2576 and PDAPP transgenic mouse models.
- Amyloid burden was quantified in various brain areas of the transgenic mice.
- Emulsion-dipped sections were utilized to confirm neuronal expression patterns.
Main Results:
- hAPP expression was highest in cortical, cerebellar, and hippocampal neurons in transgene-positive mice.
- Amyloid burden was observed in the cingulate, entorhinal, and hippocampal regions, but not the cerebellum.
- BACE expression showed a predominantly neuronal pattern, with highest levels in the cerebellum and hippocampus, independent of age or transgene presence.
Conclusions:
- hAPP and endogenous BACE expression in overlapping neuronal populations facilitate APP processing and amyloid-beta formation in transgenic models.
- Age-related and anatomical factors modulate amyloid-beta production, suggesting complex disease mechanisms.
