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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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 8

SD affects AQP4 gene and protein expression in an apoE isoform–dependent manner.

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SD affects AQP4 gene and protein expression in an apoE isoform–dependent...
(A) Heatmap analysis of bulk RNA in cortices from APPPS1:E3 and APPPS1:E4 male mice that were subjected to NS or SD, generated by hierarchical gene clustering based on groups (n = 6 per group). (B) Selected heatmap analysis results from each cluster. Heatmap z scores were calculated for each gene and plotted instead of the normalized expression values. (C) Western blot images of AQP4, SNAP25 (neuronal marker, mainly detected in the parenchyma fraction), α-SMA (vascular marker), CD31, and the β-actin compartment from single mouse brain hemispheres (half-cerebral cortex) from APPPS1:E3 and APPPS1:E4 male mice that were subjected to NS or SD (n = 4 per group). V, vessel fraction; P, parenchyma fraction. (D and E) Quantitative analysis of AQP4 expression levels after normalization to β-actin (D) or CD31 (E). Data are presented as the mean ± SEM. Significance was determined by 2-way ANOVA followed by a Tukey’s post hoc test (apoE genotype and sleep condition) (B, D, and E). *P < 0.05. See also Supplemental Table 1.