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. 2024 Jan 15;15(1):258.
doi: 10.1038/s41467-023-44520-4.

Amyloid beta 42 alters cardiac metabolism and impairs cardiac function in male mice with obesity

Liam G Hall #  1   2 , Juliane K Czeczor #  1   3 , Timothy Connor  1 , Javier Botella  1 , Kirstie A De Jong  1   4 , Mark C Renton  5 , Amanda J Genders  1   6 , Kylie Venardos  1 , Sheree D Martin  1 , Simon T Bond  1   7 , Kathryn Aston-Mourney  1 , Kirsten F Howlett  5 , James A Campbell  8 , Greg R Collier  8 , Ken R Walder  1 , Matthew McKenzie  9 , Mark Ziemann  9 , Sean L McGee  10   11
Affiliations

Amyloid beta 42 alters cardiac metabolism and impairs cardiac function in male mice with obesity

Liam G Hall et al. Nat Commun. .

Abstract

There are epidemiological associations between obesity and type 2 diabetes, cardiovascular disease and Alzheimer's disease. The role of amyloid beta 42 (Aβ42) in these diverse chronic diseases is obscure. Here we show that adipose tissue releases Aβ42, which is increased from adipose tissue of male mice with obesity and is associated with higher plasma Aβ42. Increasing circulating Aβ42 levels in male mice without obesity has no effect on systemic glucose homeostasis but has obesity-like effects on the heart, including reduced cardiac glucose clearance and impaired cardiac function. The closely related Aβ40 isoform does not have these same effects on the heart. Administration of an Aβ-neutralising antibody prevents obesity-induced cardiac dysfunction and hypertrophy. Furthermore, Aβ-neutralising antibody administration in established obesity prevents further deterioration of cardiac function. Multi-contrast transcriptomic analyses reveal that Aβ42 impacts pathways of mitochondrial metabolism and exposure of cardiomyocytes to Aβ42 inhibits mitochondrial complex I. These data reveal a role for systemic Aβ42 in the development of cardiac disease in obesity and suggest that therapeutics designed for Alzheimer's disease could be effective in combating obesity-induced heart failure.

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Conflict of interest statement

Ambetex Pty Ltd has submitted patents containing aspects of this work (PCT/AU2020/051254; PCT/AU2020/051348; PCT/AU2020/051350; PCT/AU2020/051353). LGH, JKC, JAC, GRC and SLM own equity in Ambetex Pty Ltd. The remaining authors declare no conflict of interests.

Figures

Fig. 1
Fig. 1. Ab42 is released from adipose tissue, which is increased in obesity.
a App expression in adipose tissue (Mann Whitney test, U = 6; n = 12/group), the liver (n = 10 and 9/group respectively) and skeletal muscle (Sk. musc., quadriceps; unpaired t-tests; n = 12/group) from control and obese mice. b Bace1 expression in adipose tissue (Mann Whitney test, U = 1; n = 12/group), the liver (n = 9 and 8/group, respectively) and sk. musc. (unpaired t-tests; n = 12/group) from control and obese mice. c, Psen1 expression in adipose tissue (Mann Whitney test, U = 14; n = 10 and 12/group respectively), the liver (n = 12/group) and sk. musc. (n = 12/group) from control and obese mice (unpaired t-tests). d BACE1 activity in adipose tissue (n = 12 and 10/group respectively), the liver (n = 8/group) and sk. musc. (n = 8/group) from control and obese mice (unpaired t-tests). e relative release of Aβ isoforms from adipose tissue of control and obese mice normalised for tissue weight. f absolute release of Aβ isoforms from adipose tissue of control (n = 12) and obese (n = 11) mice (Mann Whitney test, U = 6). g plasma Aβ isoforms in control (n = 12) and obese (n = 11) mice (unpaired t-test). All data are mean ± SEM. Statistical tests are two-tailed. Source data are provided in the Source Data file.
Fig. 2
Fig. 2. Aβ42 administration reprograms cardiac metabolism.
a schematic of experiment where mice were administered Aβ42 or scrambled Aβ42 (ScrAβ42; 1 μg/day i.p.) for 4 weeks and analytical procedures were performed in final two weeks. b plasma Αβ42 in mice 5 h after administration of ScrAβ42 (n = 9) or Aβ42 (n = 10; unpaired t-test). c body weight in mice administered ScrAβ42 or Aβ42. (n = 10/group). d blood glucose during an insulin tolerance test in mice administered ScrAβ42 or Aβ42 (n = 10/group). e, blood glucose during a glucose tolerance test in mice administered ScrAβ42 or Aβ42 (n = 10/group). f cardiac glucose clearance in mice administered ScrAβ42 (n = 10) or Aβ42 (n = 9; unpaired t-test). g 14C-glucose incorporation into lipids in mice administered ScrAβ42 (n = 9) or Aβ42 (n = 10; unpaired t-test). All data are mean ± SEM. Statistical tests are two-tailed. Source data are provided in the Source Data file. Elements of a are created with BioRender.com.
Fig. 3
Fig. 3. Aβ42 administration induces cardiac dysfunction.
a deceleration time in mice administered ScrAβ42 or Aβ42 (unpaired t-test; n = 7 and 9/group respectively). b E:A ratio in mice administered ScrAβ42 or Aβ42 (unpaired t-test; n = 9 and 6/group respectively). c ejection fraction in mice administered ScrAβ42 or Aβ42 (unpaired t-test; n = 9 and 10/group respectively). d fractional shortening in mice administered ScrAβ42 or Aβ42 (unpaired t-test; n = 9 and 10/group respectively). e Expression of Nppa (Mann-Whitney test, U = 8), Fap, Itga1, Rora and Fgfr1 in hearts of mice administered ScrAβ42 or Aβ42 (n = 8 and 7/group respectively). All data are mean ± SEM. Statistical tests are two-tailed. Source data are provided in the Source Data file.
Fig. 4
Fig. 4. An Aβ42 neutralising antibody prevents obesity-induced impairment of cardiac relaxation.
a schematic of experiment where mice fed a high fat diet (HFD) for 4 months and were simultaneously administered a control antibody or an Aβ42 neutralising antibody (3D6) once weekly. Analysis of cardiac function and morphology was performed at the beginning and end of the experiment. b total (n = 12 and 9/group respectively), and; c, free (n = 9 and 8/group respectively) Aβ42 in plasma of mice administered control or 3D6 antibodies (unpaired t-test). d body weight of mice administered control or 3D6 antibodies (n = 12/group). e deceleration time in mice prior to and after 4 months of high-fat feeding and antibody administration (two-way repeated measures ANOVA (time P = 0.0140, F(1,20) = 7.257) and Sidak’s multiple comparisons test P.adjusted; n = 12 and 10/group respectively). f estimated left ventricle (LV) mass in mice prior to and after 4 months of high-fat feeding and antibody administration (two-way repeated measures ANOVA (time P = 0.0010, F(1,20) = 14.93) and Sidak’s multiple comparisons test P.adjusted; n = 11/group). All data are mean ± SEM. Statistical tests are two-tailed. Source data are provided in the Source Data file. Elements of a are created with BioRender.com.
Fig. 5
Fig. 5. An Aβ42 neutralising antibody prevents further impairment of cardiac relaxation in established obesity.
a schematic of experiment where mice fed either chow or a high-fat diet (HFD) for 4 months and were administered a control antibody or an Aβ42 neutralising antibody (3D6) once weekly in the final month of the diet period. Analysis of cardiac function and morphology was performed at the beginning and of the experiment (baseline), prior to the treatment period (pre-treatment) and at the end of the treatment period (post-treatment). b body weight over time in mice fed regular chow or HFD and administered control or 3D6 antibodies (n = 12/group). c deceleration time in mice at Baseline, pre-treatment and post-treatment after 4 months of chow or high fat feeding and antibody administration (mixed-effects model (time P < 0.0001, F(2,93) = 31.56; treatment P = 0.0151, F(2,93) = 4.390) and Sidak’s multiple comparisons test P.adjusted; n = 12/group). d cardiac glucose clearance (n = 8, 9 and 9/group respectively), and; e cardiac triglycerides (TG; One-way ANOVA, P = 0.0082, F(2,31) = 5.624; n = 12, 12 and 10/group respectively) in mice fed regular chow and administered control antibody, or mice fed a high fat diet (HFD) and administered control or 3D6 antibodies. All data are mean ± SEM. Statistical tests are two-tailed. Source data are provided in the Source Data file. Elements of a are created with BioRender.com.
Fig. 6
Fig. 6. Aβ42 impairs mitochondrial transcriptional programs and accumulates in cardiac mitochondria in obesity.
a heat map of Reactome pathways reciprocally regulated in the hearts of mice from Aβ42 (Fig. 2a) and 3D6 (Fig. 3a) administration studies, determined by MITCH analysis from bulk RNA-seq data. b TCA cycle pathway rank (P.adjusted MANOVA test) and heat map of TCA cycle genes in the hearts of mice from Aβ42 and 3D6 administration studies. c pyruvate metabolism pathway rank (P.adjusted MANOVA test) and heat map of pyruvate metabolism genes in the hearts of mice from Aβ42 and 3D6 administration studies. d mitochondrial biogenesis pathway rank (P.adjusted MANOVA test) and heat map of mitochondrial biogenesis genes in the hearts of mice from Aβ42 and 3D6 administration studies. e characterisation of enriched mitochondrial fractions from hearts of chow or high fat diet (HFD)-fed mice. f Aβ42 in mitochondrial fractions isolated from hearts of chow or HFD-fed mice (unpaired t-test; n = 13 and 12/group respectively). g Aβ42 in mitochondrial fractions isolated from hearts of mice fed HFD and administered control or 3D6 antibodies (Fig. 3a; unpaired t-test; n = 8/group). All data are mean ± SEM. Statistical tests are two-tailed. Source data are provided in the Source Data file.
Fig. 7
Fig. 7. Aβ42 inhibits mitochondrial complex I in cardiomyocytes.
a Basal oxygen consumption rate (OCR) in primary mouse neonatal cardiomyocytes (NVCM) exposed to ScrAβ42 or Aβ42 (ScrAβ42 at 300 (++), 100 (+) and 0pM (−) and co-incubated with Aβ42 at 0 (−), 200 (+) and 300pM (++) for 48 hrs (one-way ANOVA (P < 0.0001; F(2,15) = 53.5) with Sidak’s repeated measures test P.adjusted; n = 6 biological replicates/group). b maximal OCR in primary NVCM exposed to ScrAβ42 or Aβ42 for 48 hrs (one-way ANOVA (P = 0.0001; F(2,15) = 31.2) with Sidak’s repeated measures test P.adjusted; n = 6 biological replicates/group). c inhibition of respiration in response to increasing concentrations of rotenone in primary NVCM exposed to ScrAβ42 or Aβ42 for 48 hrs (multiple t-tests P.adjusted; n = 5 biological replicates/group). d absolute complex I (CI) OCR in primary NVCM exposed to ScrAβ42 or Aβ42 for 48 hrs (one-way ANOVA (P < 0.0001; F(2,15) = 88.4) with Sidak’s repeated measures test P.adjusted; n = 6 biological replicates/group). e complex I (CI) OCR as a percentage of total respiratory capacity in primary NVCM exposed to ScrAβ42 or Aβ42 for 48 hrs (one-way ANOVA (P < 0.0012; F(2,15) = 10.8) with Sidak’s repeated measures test P.adjusted; n = 6 biological replicates/group). All data are mean ± SEM. All statistical tests are two-tailed. Source data are provided in the Source Data file. f schematic of proposed model whereby adipose tissue release of Aβ42 is increased in obesity resulting in higher circulating levels of Aβ42. Increased circulating Aβ42 inhibits cardiomyocyte mitochondrial ATP production and causes diastolic dysfunction, which starts the progression towards heart failure. The effects of Aβ42 on cardiomyocytes could be mediated through receptor-mediated signalling, receptor-mediated internalisation, or direct internalisation. e was created with BioRender.com.
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