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

Abstract

BackgroundThe β-secretase, BACE1, cleaves APP to initiate generation of the β-amyloid peptide, Aβ, 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 Aβ 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.Results50% BACE1 reduction reduces Aβ42, plaques, and BACE1-cleaved APP fragments in female, but not in male, 5XFAD/BACE1+/− mice. 5XFAD/BACE1+/+ females have higher levels of Aβ42 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 Aβ42 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 Aβ42 in 5XFAD/BACE1+/− males. We also developed and validated a dot blot assay with an Aβ42-selective antibody as an accurate and cost-effective alternative to ELISA for measuring cerebral Aβ42 levels.Conclusions50% BACE1 reduction lowers Aβ42 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 Aβ, 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.

Systems genetics identifies modifiers of Alzheimer’s disease risk and resilience

“…27, 2017; significant main effect of strain was observed [F(22,153) = 2.1, p = 0.01], indicating that genetic background significantly modified the Aβ42 levels across the panel. No main effect of sex was observed [F(1, 153) = 1.4, p = 0.25], in contrast to a previous report using a single genetic background suggesting the 5XFAD model preferentially affect females (Sadleir et al, 2015).…”

The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease

“…Our recent data demonstrated that synaptic store-operated calcium entry (nSOC) plays an important role in control of stability of hippocampal (Popugaeva et al, 2015; Sun et al, 2014; Zhang et al, 2015) and striatal (Wu et al, 2016) synaptic spines. In HD, mHtt binds to and sensitizes InsP 3 R1 to basal levels of InsP 3 (Tang et al, 2003), increasing Ca 2+ leakage from the ER (Tang et al, 2005; Tang et al, 2003).…”

Quantitative Comparison of Dense-Core Amyloid Plaque Accumulation in Amyloid-β Protein Precursor Transgenic Mice

“…Because the kinetics of plaque deposition have been reported to be gender-dependent [13–16], we selected cohorts containing only a single gender within each line; with this criterion, we had available tissue from female 5XFAD mice and from male mice of the other three lines. We elected to proceed with this study with the tissue currently available, as gender is only one among several factors that can influence plaque deposition or AβPP metabolism, including background strain [17], housing conditions [18, 19] and even maternal diet [20] or activity [21].…”