Connections between ApoE, sleep, and Aβ and tau pathologies in Alzheimer's disease

Abstract

In this issue of the JCI, Wang and colleagues investigate the relationship between sleep disturbances, an environmental risk factor for Alzheimer's disease (AD), and the apolipoprotein 4 (APOEε4) allele, a strong genetic risk factor for AD. The authors subjected an amyloid mouse model expressing human APOE3 or APOE4, with and without human AD-tau injection, to sleep deprivation and observed that amyloid and tau pathologies were worsened in the presence of APOE4. Moreover, decreased microglial clustering and increased dystrophic neurites around plaques were observed in sleep-deprived APOE4 mice. In addition, aquaporin 4, important for clearing amyloid-β through the glymphatic system, was reduced and less polarized to astrocytic endfeet. These APOE4-induced changes caused alterations in sleep behavior during recovery from sleep deprivation, suggesting a feed-forward cycle of sleep disturbance and increased AD pathology that can further disrupt sleep in the presence of APOE4.

Figure 1. Sleep deprivation in the context of APOE4 results in a feed-forward loop that perpetuates neuropathological features and further disrupts sleep.

The APPPS1:E4 mouse model develops pathology, including dystrophic neurites around amyloid plaques. Sleep deprivation in APPPS1:E4 mouse models results in microglial dysfunction that worsens amyloid and tau pathology, leading to further sleep disruption in a feed-forward loop. Structural changes include increases in the amyloid plaque area and fewer microglia clusters around plaques, which causes greater dystrophic neurite formation. In the presence of AD-tau, increased dystrophic neurites lead to further tau seeding and spreading. In addition, altered astrocyte function and reduced polarization of AQP4 to endfeet on blood vessels can impair glymphatic clearance of Aβ and lead to a higher plaque load. The expression of microglial homeostatic genes is reduced, which could further increase the plaque load, decrease microglial clustering, and induce astrocytic changes such as AQP4 reduction. APOE4 may also directly affect astrocyte function, as it is highly expressed in astrocytes.