APOE-ε4 synergizes with sleep disruption to accelerate Aβ deposition and Aβ-associated tau seeding and spreading
Chanung Wang, … , Jason D. Ulrich, David M. Holtzman
Chanung Wang, … , Jason D. Ulrich, David M. Holtzman
Published June 6, 2023
Citation Information: J Clin Invest. 2023;133(14):e169131. https://doi.org/10.1172/JCI169131.
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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 2

SD in APPPS1 mice increases fibrillar plaques in the presence of apoE4 but not apoE3.

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SD in APPPS1 mice increases fibrillar plaques in the presence of apoE4 b...
(A) Representative images of brain sections stained with X-34 dye, which recognizes only fibrillar plaques. Brain sections were from APPPS1:E3 and APPPS1:E4 mice from the NS and SD groups. Scale bars: 400 μm. Original magnification, ×1.25 (insets). (B–D) Quantification of the percentage of area covered by X-34 staining in cortex (B), hippocampus (C), and thalamus (D) (n = 12–15 per group). 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, **P < 0.01, and ***P < 0.001. No other statistical comparisons are significant unless indicated. See also Supplemental Table 1.