A beta reduction in BACE1 heterozygous null 5XFAD mice is associated with transgenic APP level

作者：Sadleir Katherine R; Eimer William A; Cole Sarah L; Vassar Robert^*

来源：Molecular Neurodegeneration, 2015, 10(1): 1.

DOI：10.1186/1750-1326-10-1

• beta-secretase
• Amyloid precursor protein
• Alzheimer's disease
• APP transgenic mouse models
• 5XFAD
• BACE1 heterozygous
• Amyloid
• A beta
• Dot blot
• Estrogen response element

Background: The beta-secretase, BACE1, cleaves APP to initiate generation of the beta-amyloid peptide, A beta, that comprises amyloid plaques in Alzheimer's disease (AD). Reducing BACE1 activity is an attractive therapeutic approach to AD, but complete inhibition of BACE1 could have mechanism-based side-effects as BACE1(-/-) mice show deficits in axon guidance, myelination, memory, and other neurological processes. Since BACE1(+/-) mice appear normal there is interest in determining whether 50% reduction in BACE1 is potentially effective in preventing or treating AD. APP transgenic mice heterozygous for BACE1 have decreased A beta but the extent of reduction varies greatly from study to study. Here we assess the effects of 50% BACE1 reduction on the widely used 5XFAD mouse model of AD.
Results: 50% BACE1 reduction reduces A beta 42, plaques, and BACE1-cleaved APP fragments in female, but not in male, 5XFAD/ BACE1(+/-) mice. 5XFAD/ BACE1(+/+) females have higher levels of A beta 42 and steady-state transgenic APP than males, likely caused by an estrogen response element in the transgene Thy-1 promoter. We hypothesize that higher transgenic APP level in female 5XFAD mice causes BACE1 to no longer be in excess over APP so that 50% BACE1 reduction has a significant A beta 42 lowering effect. In contrast, the lower APP level in 5XFAD males allows BACE1 to be in excess over APP even at 50% BACE1 reduction, preventing lowering of A beta 42 in 5XFAD/ BACE1(+/-) males. We also developed and validated a dot blot assay with an A beta 42-selective antibody as an accurate and cost-effective alternative to ELISA for measuring cerebral A beta 42 levels.
Conclusions: 50% BACE1 reduction lowers A beta 42 in female 5XFAD mice only, potentially because BACE1 is not in excess over APP in 5XFAD females with higher transgene expression, while BACE1 is in excess over APP in 5XFAD males with lower transgene expression. Our results suggest that greater than 50% BACE1 inhibition might be necessary to significantly lower A beta, given that BACE1 is likely to be in excess over APP in the human brain. Additionally, in experiments using the 5XFAD mouse model, or other Thy-1 promoter transgenic mice, equal numbers of male and female mice should be used, in order to avoid artifactual gender-related differences.

• 出版日期2015-1-7
• 单位西北大学