APOE-ε4 synergizes with sleep disruption to accelerate Aβ deposition and Aβ-associated tau seeding and spreading
Chanung Wang, Aishwarya Nambiar, Michael R. Strickland, Choonghee Lee, Samira Parhizkar, Alec C. Moore, Erik S. Musiek, Jason D. Ulrich, David M. Holtzman
Chanung Wang, Aishwarya Nambiar, Michael R. Strickland, Choonghee Lee, Samira Parhizkar, Alec C. Moore, Erik S. Musiek, Jason D. Ulrich, David M. Holtzman
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Research Article Neuroscience

APOE-ε4 synergizes with sleep disruption to accelerate Aβ deposition and Aβ-associated tau seeding and spreading

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia. The APOE-ε4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset AD. The APOE genotype modulates the effect of sleep disruption on AD risk, suggesting a possible link between apoE and sleep in AD pathogenesis, which is relatively unexplored. We hypothesized that apoE modifies Aβ deposition and Aβ plaque–associated tau seeding and spreading in the form of neuritic plaque–tau (NP-tau) pathology in response to chronic sleep deprivation (SD) in an apoE isoform–dependent fashion. To test this hypothesis, we used APPPS1 mice expressing human APOE-ε3 or -ε4 with or without AD-tau injection. We found that SD in APPPS1 mice significantly increased Aβ deposition and peri-plaque NP-tau pathology in the presence of APOE4 but not APOE3. SD in APPPS1 mice significantly decreased microglial clustering around plaques and aquaporin-4 (AQP4) polarization around blood vessels in the presence of APOE4 but not APOE3. We also found that sleep-deprived APPPS1:E4 mice injected with AD-tau had significantly altered sleep behaviors compared with APPPS1:E3 mice. These findings suggest that the APOE-ε4 genotype is a critical modifier in the development of AD pathology in response to SD.

Authors

Chanung Wang, Aishwarya Nambiar, Michael R. Strickland, Choonghee Lee, Samira Parhizkar, Alec C. Moore, Erik S. Musiek, Jason D. Ulrich, David M. Holtzman

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Figure 6

SD in AD-tau–injected APPPS1 mice significantly affects microglia clustering and neuritic dystrophy formation in an apoE isoform–dependent manner.

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SD in AD-tau–injected APPPS1 mice significantly affects microglia cluste...
(A and B) Confocal image of IBA1-labeled microglia (green) and BACE-labeled neuritic dystrophy (magenta) costained around X34+ plaques (blue) in ipsi- (A) and contralateral (B) cortices from APPPS1:E3 and APPPS1:E4 mice from the NS or SD groups (n = 13–15 per group). Scale bars: 20 μm. (C–H) Quantification of the number of microglia surrounding plaques in the ipsi- and contralateral cortices (C and D, respectively), hippocampi (E and F, respectively), and thalami (G and H, respectively) of AD-tau–injected APPPS1:E3 and APPPS1:E4 mice. (I–N) Quantification of the percentage of BACE1+ voxels within 15 μm of plaques in the ipsi- and contralateral cortices (I and J, respectively), hippocampi (K and L, respectively), and thalami (M and N, respectively) of AD-tau–injected APPPS1:E3 and APPPS1:E4 mice. Data are presented as the mean ± SEM. Significance was determined by 3-way ANOVA with Šidák’s multiple-comparison test (sex, apoE genotype, and sleep condition). *P < 0.05 and **P < 0.01. See also Supplemental Table 1.