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Cited by 213Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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

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Sadleir, Katherine R, Eimer, William A, Cole, Sarah L, Vassar, Robert·2015·Molecular Neurodegeneration
DOI 10.1186/1750-1326-10-1PMC PMC4297413
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Abstract

BACKGROUND: The 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. RESULTS: 50% 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. CONCLUSIONS: 50% 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.

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Figure 1 BACE1 levels are reduced by ~50% in 5XFAD/BACE1 +/− mice. (A) 20 μg of protein/lane of brain homogenates of 4, 6, and 9 month-old 5XFAD/BACE1+/+, 5XFAD/BACE1+/− or 5XFAD/BACE1−/− (as a negative control) female (F) and male (M) mice were separated by SDS-PAGE, transferred onto PVDF membrane, stained with Ponceau S, and incubated with BACE-Cat1 monospecific antibody against BACE1 [28] followed by HRP-conjugated secondary antibody and chemiluminescence imaging. Representative BACE1 immunoblot and Ponceau S staining of brain homogenates from 4 month-old mice is shown. Note the absence of BACE1 immunosignal in the BACE1−/− lane. (B-D) Relative quantification of BACE1 levels in brain homogenates of 4, 6, and 9 month-old female and male 5XFAD/BACE1+/+, 5XFAD/BACE1+/− or 5XFAD/BACE1−/− mice. BACE1 immunosignals were normalized to Ponceau S staining intensity per lane, averaged for each group, then presented as percentage of mean female 5XFAD/BACE1+/+ BACE1 level. At all ages, BACE1 level is significantly reduced by ~50% in 5XFAD/BACE1+/− mice compared to 5XFAD/BACE1+/+ mice, and there is no difference in BACE1 level between male and female 5XFAD/BACE1+/+ or male and female 5XFAD/BACE1+/− mice.
Figure 1 BACE1 levels are reduced by ~50% in 5XFAD/BACE1 +/− mice. (A) 20 μg of protein/lane of brain homogenates of 4, 6, and 9 month-old 5XFAD/BACE1+/+, 5XFAD/BACE1+/− or 5XFAD/BACE1−/− (as a negative control) female (F) and male (M) mice were separated by SDS-PAGE, transferred onto PVDF membrane, stained with Ponceau S, and incubated with BACE-Cat1 monospecific antibody against BACE1 [28] followed by HRP-conjugated secondary antibody and chemiluminescence imaging. Representative BACE1 immunoblot and Ponceau S staining of brain homogenates from 4 month-old mice is shown. Note the absence of BACE1 immunosignal in the BACE1−/− lane. (B-D) Relative quantification of BACE1 levels in brain homogenates of 4, 6, and 9 month-old female and male 5XFAD/BACE1+/+, 5XFAD/BACE1+/− or 5XFAD/BACE1−/− mice. BACE1 immunosignals were normalized to Ponceau S staining intensity per lane, averaged for each group, then presented as percentage of mean female 5XFAD/BACE1+/+ BACE1 level. At all ages, BACE1 level is significantly reduced by ~50% in 5XFAD/BACE1+/− mice compared to 5XFAD/BACE1+/+ mice, and there is no difference in BACE1 level between male and female 5XFAD/BACE1+/+ or male and female 5XFAD/BACE1+/− mice.CC BY · PubMed Central
Figure 2 Dot blot assay effectively measures relative levels of cerebral Aβ42. (A) Validation of blot assay. Brain homogenates from 6 month-old female mice were extracted overnight in GuHCl, then spotted in triplicate on nitrocellulose membrane, dried, stained with Ponceau S, and incubated with anti-Aβ42 antibody followed by HRP-conjugated secondary antibody and chemiluminescence imaging. To subtract non-specific background, a duplicate membrane was prepared in the same way, except that the anti-Aβ42 primary antibody was not included (secondary only). (+) or (−) indicate 5XFAD or non-transgenic genotypes, respectively; BACE1 genotype is indicated below 5XFAD genotype. (B) Relative quantification of the Aβ42 dot blot in (A). The secondary only background was subtracted from the Aβ42 immunosignal, then the difference was normalized to Ponceau S staining intensity and triplicates averaged. Group means were calculated and presented as percentages of the 5XFAD/BACE1+/+ female group. The Aβ42 level in 5XFAD/BACE1−/− females is not significantly different than that of non-Tg BACE1+/+ females, indicating that the anti-Aβ42 antibody does not recognize full-length APP. 5XFAD/BACE1+/− mice have significantly less Aβ42 than 5XFAD/BACE1+/+ mice and significantly more Aβ42 than 5XFAD/BACE1−/− mice. n = 6 per genotype, except n = 2 for non-Tg/BACE1−/−. (C) Aβ42 dot blot demonstrating the dynamic range of the assay. Brain homogenates from female 4, 6, and 9 month-old 5XFAD/BACE1+/+ (n = 6), 6 month-old non-Tg BACE1+/+ (n = 6), and BACE1−/− (n = 2) mice were prepared as in (A), except homogenates were extracted in GuHCl for 72 rather than 24 hrs, which eliminated the IgG background. Since there was no secondary only signal, this blot is not shown, or used for correction. (D) Relative quantification of the Aβ42 dot blot in (C) shows at least a 10-fold dynamic range of detection, and clear differences are observed between groups.
Figure 2 Dot blot assay effectively measures relative levels of cerebral Aβ42. (A) Validation of blot assay. Brain homogenates from 6 month-old female mice were extracted overnight in GuHCl, then spotted in triplicate on nitrocellulose membrane, dried, stained with Ponceau S, and incubated with anti-Aβ42 antibody followed by HRP-conjugated secondary antibody and chemiluminescence imaging. To subtract non-specific background, a duplicate membrane was prepared in the same way, except that the anti-Aβ42 primary antibody was not included (secondary only). (+) or (−) indicate 5XFAD or non-transgenic genotypes, respectively; BACE1 genotype is indicated below 5XFAD genotype. (B) Relative quantification of the Aβ42 dot blot in (A). The secondary only background was subtracted from the Aβ42 immunosignal, then the difference was normalized to Ponceau S staining intensity and triplicates averaged. Group means were calculated and presented as percentages of the 5XFAD/BACE1+/+ female group. The Aβ42 level in 5XFAD/BACE1−/− females is not significantly different than that of non-Tg BACE1+/+ females, indicating that the anti-Aβ42 antibody does not recognize full-length APP. 5XFAD/BACE1+/− mice have significantly less Aβ42 than 5XFAD/BACE1+/+ mice and significantly more Aβ42 than 5XFAD/BACE1−/− mice. n = 6 per genotype, except n = 2 for non-Tg/BACE1−/−. (C) Aβ42 dot blot demonstrating the dynamic range of the assay. Brain homogenates from female 4, 6, and 9 month-old 5XFAD/BACE1+/+ (n = 6), 6 month-old non-Tg BACE1+/+ (n = 6), and BACE1−/− (n = 2) mice were prepared as in (A), except homogenates were extracted in GuHCl for 72 rather than 24 hrs, which eliminated the IgG background. Since there was no secondary only signal, this blot is not shown, or used for correction. (D) Relative quantification of the Aβ42 dot blot in (C) shows at least a 10-fold dynamic range of detection, and clear differences are observed between groups.CC BY · PubMed Central
Figure 3 Aβ42 levels are reduced in female but not male 5XFAD/BACE1 +/− mice. (A-C) Aβ42 dot blot assays were performed using GuHCl extracted brain homogenates from 4 (A), 6 (B) and 9 (C) month-old 5XFAD/BACE1+/+ and 5XFAD/BACE1+/− male and female mice (n = 6–17 mice per genotype per sex) and relative quantifications determined and presented as percentages of the mean female 5XFAD/BACE1+/+ Aβ42 level. 5XFAD/BACE1+/− females had ~30-40% less Aβ42 than 5XFAD/BACE1+/+ females. In contrast, Aβ42 levels of male 5XFAD/BACE1+/− and 5XFAD/BACE1+/+ were indistinguishable, and both were significantly less than that of 5XFAD/BACE1+/+ females. (D) To confirm the relative Aβ42 quantifications generated by the dot blot assay, Aβ42 levels in the brain homogenates from the 6 month-old cohort shown in (B) were quantified by commercial Aβ42 ELISA (Invitrogen), yielding very similar results. (E) Aβ42 measured by ELISA correlates significantly with Aβ42 measured by dot blot, further validating this method. (F) To determine the range and sensitivity of the Aβ42 dot blot assay, known quantities of synthetic Aβ42 were spiked into a transgene-negative BACE1−/− homogenate, which was then GuHCl extracted and analyzed by dot blot (upper blot). Numbers above the blot indicate concentrations of Aβ42 in ng/mg total brain homogenate protein. (G) Aβ42 dot blot signals from (F) were corrected by subtracting the secondary antibody-alone background, converted to percentage of intensity of 1000 ng Aβ42/mg protein (y-axis), and plotted as a function of known Aβ42 concentration (x-axis). The dot blot is accurate through at least a 500-fold concentration range, with very good linearity from 1.9-250 ng Aβ42/mg total protein, as shown by the blue section of the curve (expanded in the inset). Error bars (SEM) are plotted in both graphs, but are too small to be seen except in the expanded inset.
Figure 3 Aβ42 levels are reduced in female but not male 5XFAD/BACE1 +/− mice. (A-C) Aβ42 dot blot assays were performed using GuHCl extracted brain homogenates from 4 (A), 6 (B) and 9 (C) month-old 5XFAD/BACE1+/+ and 5XFAD/BACE1+/− male and female mice (n = 6–17 mice per genotype per sex) and relative quantifications determined and presented as percentages of the mean female 5XFAD/BACE1+/+ Aβ42 level. 5XFAD/BACE1+/− females had ~30-40% less Aβ42 than 5XFAD/BACE1+/+ females. In contrast, Aβ42 levels of male 5XFAD/BACE1+/− and 5XFAD/BACE1+/+ were indistinguishable, and both were significantly less than that of 5XFAD/BACE1+/+ females. (D) To confirm the relative Aβ42 quantifications generated by the dot blot assay, Aβ42 levels in the brain homogenates from the 6 month-old cohort shown in (B) were quantified by commercial Aβ42 ELISA (Invitrogen), yielding very similar results. (E) Aβ42 measured by ELISA correlates significantly with Aβ42 measured by dot blot, further validating this method. (F) To determine the range and sensitivity of the Aβ42 dot blot assay, known quantities of synthetic Aβ42 were spiked into a transgene-negative BACE1−/− homogenate, which was then GuHCl extracted and analyzed by dot blot (upper blot). Numbers above the blot indicate concentrations of Aβ42 in ng/mg total brain homogenate protein. (G) Aβ42 dot blot signals from (F) were corrected by subtracting the secondary antibody-alone background, converted to percentage of intensity of 1000 ng Aβ42/mg protein (y-axis), and plotted as a function of known Aβ42 concentration (x-axis). The dot blot is accurate through at least a 500-fold concentration range, with very good linearity from 1.9-250 ng Aβ42/mg total protein, as shown by the blue section of the curve (expanded in the inset). Error bars (SEM) are plotted in both graphs, but are too small to be seen except in the expanded inset.CC BY · PubMed Central
Figure 4 Amyloid plaques are reduced in female but not male 5XFAD/BACE1 +/− mice. Free-floating 30 μm brain sections from 6 month-old male and female 5XFAD/BACE1+/+ and 5XFAD/BACE1+/− mice were co-stained with clone 3D6, an antibody to the N-terminus of Aβ (green), anti-BACE1 antibody (red), and DAPI (blue) and imaged by fluorescence confocal microscopy. Three mice of each sex and genotype combination were analyzed for a total of twelve mice, and all images were captured using identical confocal camera and laser configurations. The representative images of mid-dorsal cortex and hippocampus shown here are from individuals that had Aβ42 dot blot values near the mean of each group. Amyloid plaque densities in Layer 5 of the cortex correlate well with Aβ42 levels determined by dot blot. Female 5XFAD/BACE1+/+ mice have the highest plaque density, with 5XFAD/BACE1+/− females showing a marked reduction in amyloid deposits by comparison. In contrast, male 5XFAD/BACE1+/+ and 5XFAD/BACE1+/− mice had similar plaque densities, and both had fewer plaques than 5XFAD/BACE1+/+ female mice. These histological results support our biochemical data showing that Aβ42 levels are reduced in 5XFAD/BACE1+/− female, but not male, mice (Figure 3). Size bar represents 100 μm.
Figure 4 Amyloid plaques are reduced in female but not male 5XFAD/BACE1 +/− mice. Free-floating 30 μm brain sections from 6 month-old male and female 5XFAD/BACE1+/+ and 5XFAD/BACE1+/− mice were co-stained with clone 3D6, an antibody to the N-terminus of Aβ (green), anti-BACE1 antibody (red), and DAPI (blue) and imaged by fluorescence confocal microscopy. Three mice of each sex and genotype combination were analyzed for a total of twelve mice, and all images were captured using identical confocal camera and laser configurations. The representative images of mid-dorsal cortex and hippocampus shown here are from individuals that had Aβ42 dot blot values near the mean of each group. Amyloid plaque densities in Layer 5 of the cortex correlate well with Aβ42 levels determined by dot blot. Female 5XFAD/BACE1+/+ mice have the highest plaque density, with 5XFAD/BACE1+/− females showing a marked reduction in amyloid deposits by comparison. In contrast, male 5XFAD/BACE1+/+ and 5XFAD/BACE1+/− mice had similar plaque densities, and both had fewer plaques than 5XFAD/BACE1+/+ female mice. These histological results support our biochemical data showing that Aβ42 levels are reduced in 5XFAD/BACE1+/− female, but not male, mice (Figure 3). Size bar represents 100 μm.CC BY · PubMed Central
Figure 5 BACE1-cleaved APP fragments sAPPβ and C99 are reduced in female but not male 5XFAD/BACE1 +/− mice. (A) Representative sAPPβ immunoblot and Ponceau S staining of brain homogenates from 4 month-old male (M) and female (F) mice. Note the minimal sAPPβ signal in the 5XFAD/BACE1−/− lane; residual band likely results from minor cross-reactivity to sAPPα. (B-D) Relative quantifications of sAPPβ immunoblot signals from 5XFAD/BACE1+/+ and 5XFAD/BACE1+/− mice. At 4 months of age there is no statistical difference in sAPPβ levels between the sexes or genotypes. However, at 6 and 9 months of age 5XFAD/BACE1+/− females show trends toward lower sAPPβ levels than 5XFAD/BACE1+/+ females, mirroring the significant reduction in Aβ42 levels. sAPPβ levels in 6 and 9 month-old 5XFAD/BACE1+/− and 5XFAD/BACE1+/+ male are indistinguishable, and significantly less than in 5XFAD/BACE1+/+ females. (E) Representative of C99 immunoblot and Ponceau S staining of brain homogenates from 9 month-old male (M) and female (F) mice. The doublet bands reflect the phosphorylation state of the APP C-terminal fragments. The lower doublet represents the α-secretase-cleaved APP C-terminal fragment C83. Note the absence of the C99 signal in the 5XFAD/BACE1−/− lane. (F-H) Relative quantification of C99 immunoblot signals from male and female 5XFAD/BACE1+/+ and 5XFAD/BACE1+/− mice. At all ages, 5XFAD/BACE1+/− females have lower levels of C99 than 5XFAD/BACE1+/+ females, but this difference reaches statistical significance only at 4 months. In contrast, C99 levels are not significantly different between 5XFAD/BACE1+/+ and 5XFAD/BACE1+/− males at any age. At 4 and 6 months of age, 5XFAD/BACE1+/+ males have significantly less C99 than 5XFAD/BACE1+/+ females, but at 9 months the decrease does not reach statistical significance due to large variation in the female cohort. Overall, the patterns of sAPPβ and C99 levels correlate with those of Aβ42 levels for the different genotypes and genders.
Figure 5 BACE1-cleaved APP fragments sAPPβ and C99 are reduced in female but not male 5XFAD/BACE1 +/− mice. (A) Representative sAPPβ immunoblot and Ponceau S staining of brain homogenates from 4 month-old male (M) and female (F) mice. Note the minimal sAPPβ signal in the 5XFAD/BACE1−/− lane; residual band likely results from minor cross-reactivity to sAPPα. (B-D) Relative quantifications of sAPPβ immunoblot signals from 5XFAD/BACE1+/+ and 5XFAD/BACE1+/− mice. At 4 months of age there is no statistical difference in sAPPβ levels between the sexes or genotypes. However, at 6 and 9 months of age 5XFAD/BACE1+/− females show trends toward lower sAPPβ levels than 5XFAD/BACE1+/+ females, mirroring the significant reduction in Aβ42 levels. sAPPβ levels in 6 and 9 month-old 5XFAD/BACE1+/− and 5XFAD/BACE1+/+ male are indistinguishable, and significantly less than in 5XFAD/BACE1+/+ females. (E) Representative of C99 immunoblot and Ponceau S staining of brain homogenates from 9 month-old male (M) and female (F) mice. The doublet bands reflect the phosphorylation state of the APP C-terminal fragments. The lower doublet represents the α-secretase-cleaved APP C-terminal fragment C83. Note the absence of the C99 signal in the 5XFAD/BACE1−/− lane. (F-H) Relative quantification of C99 immunoblot signals from male and female 5XFAD/BACE1+/+ and 5XFAD/BACE1+/− mice. At all ages, 5XFAD/BACE1+/− females have lower levels of C99 than 5XFAD/BACE1+/+ females, but this difference reaches statistical significance only at 4 months. In contrast, C99 levels are not significantly different between 5XFAD/BACE1+/+ and 5XFAD/BACE1+/− males at any age. At 4 and 6 months of age, 5XFAD/BACE1+/+ males have significantly less C99 than 5XFAD/BACE1+/+ females, but at 9 months the decrease does not reach statistical significance due to large variation in the female cohort. Overall, the patterns of sAPPβ and C99 levels correlate with those of Aβ42 levels for the different genotypes and genders.CC BY · PubMed Central
Figure 6 Female 5XFAD mice of either BACE1 +/+ or BACE1 +/− genotypes have higher steady-state transgenic APP levels than males. (A) Representative transgenic APP immunoblot (6E10) and Ponceau S staining of brain homogenates from 4 month old male (M) and female (F) mice. Note the high level of APP in the 5XFAD/BACE1−/− lane. (B-D) Relative quantifications of transgenic APP immunoblot signals. At all ages, steady-state transgenic APP levels are higher in 5XFAD/BACE1+/− and 5XFAD/BACE1+/+ females than in corresponding males. Additionally, there is a trend toward higher transgenic APP levels in 5XFAD/BACE1+/− compared to 5XFAD/BACE1+/+ mice that becomes significant at 9 months, which could result from less BACE1 cleavage in the BACE1+/− genotype. (E) Representative APP immunoblot (C-terminal APP antibody) and Ponceau S staining of brain homogenates from 6 month old 5XFAD/BACE1+/+ (+) and non-Tg/BACE1+/+ (−) mice to measure both human and mouse APP. (F) Relative quantifications of APP immunoblot signals in (E) demonstrates that while non-Tg males and females have equal levels of endogenous APP, 5XFAD females have significantly higher APP levels than 5XFAD males, a result that is consistent with the 6E10 immunoblot data showing elevated transgenic APP levels in 5XFAD females. n = 9–14 mice per sex per genotype. (G) Schematic diagram of murine Thy-1 promoter transgene cassette with 5’ upstream sequence showing estrogen resonse element (ERE). The APP or PS1 coding regions are inserted into the XhoI site. Thy-1 gene exons are shaded blue. Base-pair (bp) numbering is relative to the transcriptional start site for Thy-1 exon 1a [32]. The ERE is located from −1116 bp to −1104 bp in the 5’ upstream regulatory region of the Thy-1 promoter. The one bp deviation of the Thy-1 ERE at position +6 could be overcome by the flanking A-T rich sequence, which enhances ERE transcriptional potency in vivo[33].
Figure 6 Female 5XFAD mice of either BACE1 +/+ or BACE1 +/− genotypes have higher steady-state transgenic APP levels than males. (A) Representative transgenic APP immunoblot (6E10) and Ponceau S staining of brain homogenates from 4 month old male (M) and female (F) mice. Note the high level of APP in the 5XFAD/BACE1−/− lane. (B-D) Relative quantifications of transgenic APP immunoblot signals. At all ages, steady-state transgenic APP levels are higher in 5XFAD/BACE1+/− and 5XFAD/BACE1+/+ females than in corresponding males. Additionally, there is a trend toward higher transgenic APP levels in 5XFAD/BACE1+/− compared to 5XFAD/BACE1+/+ mice that becomes significant at 9 months, which could result from less BACE1 cleavage in the BACE1+/− genotype. (E) Representative APP immunoblot (C-terminal APP antibody) and Ponceau S staining of brain homogenates from 6 month old 5XFAD/BACE1+/+ (+) and non-Tg/BACE1+/+ (−) mice to measure both human and mouse APP. (F) Relative quantifications of APP immunoblot signals in (E) demonstrates that while non-Tg males and females have equal levels of endogenous APP, 5XFAD females have significantly higher APP levels than 5XFAD males, a result that is consistent with the 6E10 immunoblot data showing elevated transgenic APP levels in 5XFAD females. n = 9–14 mice per sex per genotype. (G) Schematic diagram of murine Thy-1 promoter transgene cassette with 5’ upstream sequence showing estrogen resonse element (ERE). The APP or PS1 coding regions are inserted into the XhoI site. Thy-1 gene exons are shaded blue. Base-pair (bp) numbering is relative to the transcriptional start site for Thy-1 exon 1a [32]. The ERE is located from −1116 bp to −1104 bp in the 5’ upstream regulatory region of the Thy-1 promoter. The one bp deviation of the Thy-1 ERE at position +6 could be overcome by the flanking A-T rich sequence, which enhances ERE transcriptional potency in vivo[33].CC BY · PubMed Central

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Metadata

Authors
Sadleir, K. R., Eimer, W. A., Cole, S. L., & Vassar, R.
Affiliations
Northwestern University (US)
Corresponding author
Vassar, Robert
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2015-01-07
Volume
10
Issue
1
Pages
1-1
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/1750-1326-10-1
PMC
PMC4297413
OpenAlex
W2137860879
Cited by
213
References
45
Citations by year
2026: 15 · 2025: 18 · 2024: 14 · 2023: 12 · 2022: 12 · 2021: 42 · 2020: 18 · 2019: 22 · 2018: 18 · 2017: 22 · 2016: 18 · 2015: 2
FWCI
14.74
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Northwestern University (CA060553, NCI CA060553)
  • National Institutes of Health (CA-060553, AG022560, NCI CA060553)
  • National Institute on Aging (RF1AG022560, R01AG030142, R01AG022560, 5T32AG00026, F32AG033445)
  • National Cancer Institute (CA 060553, NCI CA060553, P30CA060553)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
BACE1, amyloid-beta, amyloid-beta 42, 5xFAD mice, Alzheimer's disease, sex differences, estrogen response element, dot blot, amyloid plaques, BACE1 inhibition, axon guidance, myelination, memory impairment
MeSH terms
Alzheimer Disease, Animals, Brain, Disease Models, Animal, Heterozygote, Humans, Memory, Mice, Transgenic, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Mice, Knockout, Amyloid Precursor Protein Secretases, Plaque, Amyloid

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