A promising new therapeutic target for the treatment of Alzheimer's disease (AD) is the circadian system. Although patients with AD are known to have abnormal circadian rhythms and suffer sleep disturbances, the role of the molecular clock in regulating amyloid‐beta (Aβ) pathology is still poorly understood. Here, we explored how the circadian repressors REV‐ERBα and β affected Aβ clearance in mouse microglia. We discovered that, at Circadian time 4 (CT4), microglia expressed higher levels of the master clock protein BMAL1 and more rapidly phagocytosed fibrillary Aβ1‐42 (fAβ1‐42) than at CT12. BMAL1 directly drives transcription of REV‐ERB proteins, which are implicated in microglial activation. Interestingly, pharmacological inhibition of REV‐ERBs with the small molecule antagonist SR8278 or genetic knockdown of REV‐ERBs‐accelerated microglial uptake of fAβ1‐42 and increased transcription of BMAL1. SR8278 also promoted microglia polarization toward a phagocytic M2‐like phenotype with increased P2Y12 receptor expression. Finally, constitutive deletion of Rev‐erbα in the 5XFAD model of AD decreased amyloid plaque number and size and prevented plaque‐associated increases in disease‐associated microglia markers including TREM2, CD45, and Clec7a. Altogether, our work suggests a novel strategy for controlling Aβ clearance and neuroinflammation by targeting REV‐ERBs and provides new insights into the role of REV‐ERBs in AD.

ObjectiveThe purpose of this study was to analyze the relationship between fracture pattern and the development of acute radiculopathy after osteoporotic lumbar compression fracture.MethodsThis study included 59 patients who underwent bone cement augmentation for osteoporotic compression fracture below the L2 level, which can lead to radiculopathic radiating pain. The patients were divided into two groups according to the presence of radiculopathy (group A : back pain only; group B : back pain with newly developed radiating pain). We categorized compression fractures into three types by the position of the fracture line. The incidence of newly developed radiculopathy was examined retrospectively for each compression fracture type.ResultsThe overall incidence of newly developed leg pain (group B) was 25%, and the frequency increased with descending spinal levels (L2 : 0%, L3 : 22%, L4 : 43%, and L5 : 63%). The back pain-only group (group A) had mostly superior-type fractures. On the other hand, the back pain with radiculopathy group (group B) had mostly inferior-type fractures. Most patients in group B showed significant relief of leg pain as well as back pain after bone cement augmentation.ConclusionThe incidence of a newly developed, radiating pain after osteoporotic compression fractures increased gradually from the L3 to L5 levels. Most of these fractures were of the inferior type, and the bone cement augmentation procedures seemed to be sufficient for relief of both back and radiating pain.

14-3-3γ plays diverse roles in different aspects of cellular processes. Especially in the brain where 14-3-3γ is enriched, it has been reported to be involved in neurological and psychiatric diseases (e.g. Williams-Beuren syndrome and Creutzfeldt-Jakob disease). However, behavioral abnormalities related to 14-3-3γ deficiency are largely unknown. Here, by using 14-3-3γ deficient mice, we found that homozygous knockout mice were prenatally lethal, and heterozygous mice showed developmental delay relative to wild-type littermate mice. In addition, in behavioral analyses, we found that 14-3-3γ heterozygote mice display hyperactive and depressive-like behavior along with more sensitive responses to acute stress than littermate control mice. These results suggest that 14-3-3γ levels may be involved in the developmental manifestation of related neuropsychiatric diseases. In addition, 14-3-3γ heterozygote mice may be a potential model to study the molecular pathophysiology of neuropsychiatric symptoms.