No abstract

Late-onset Alzheimer’s disease (AD) remains a medical mystery. Recent studies have linked it to impaired repair of aged neurons. Potential involvement of interleukin33 (IL33) in AD has been reported. Here we show that IL33, which was expressed by up to 75% astrocytes in the aged brains, was critical for repair of aged neurons. Mice lacking Il33 gene (Il33−/−) developed AD-like disease after 60–80 weeks, which was characterized by tau abnormality and a heavy loss of neurons/neurites in the cerebral cortex and hippocampus accompanied with cognition/memory impairment. We detected an abrupt aging surge in the cortical and hippocampal neurons at middle age (40 weeks). To counter the aging surge, wild-type mice rapidly upregulated repair of DNA double-strand breaks (DSBs) and autophagic clearance of cellular wastes in these neurons. Il33−/− mice failed to do so, but instead went on to develop rapid accumulation of abnormal tau, massive DSBs and abnormal autophagic vacuoles in these neurons. Thus, uncontrolled neuronal aging surge at middle age due to lack of IL33 resulted in neurodegeneration and late-onset AD-like symptome in Il33−/− mice. Our study also suggests that the aging surge is a time to search for biomarkers for early diagnosis of AD before massive neuron loss.

Human linkage studies suggest that craniofacial deformities result from either genetic mutations related to cholesterol metabolism or high-cholesterol maternal diets. However, little is known about the precise roles of intracellular cholesterol metabolism in the development of craniofacial bones, the majority of which are formed through intramembranous ossification. Here, we show that an altered cholesterol metabolic status results in abnormal osteogenesis through dysregulation of primary cilium formation during bone formation. We found that cholesterol metabolic aberrations, induced through disruption of either Dhcr7 (which encodes an enzyme involved in cholesterol synthesis) or Insig1 and Insig2 (which provide a negative feedback mechanism for cholesterol biosynthesis), result in osteoblast differentiation abnormalities. Notably, the primary cilia responsible for sensing extracellular cues were altered in number and length through dysregulated ciliary vesicle fusion in Dhcr7 and Insig1/2 mutant osteoblasts. As a consequence, WNT/β-catenin and hedgehog signaling activities were altered through dysregulated primary cilium formation. Strikingly, the normalization of defective cholesterol metabolism by simvastatin, a drug used in the treatment of cholesterol metabolic aberrations, rescued the abnormalities in both ciliogenesis and osteogenesis in vitro and in vivo. Thus, our results indicate that proper intracellular cholesterol status is crucial for primary cilium formation during skull formation and homeostasis.Bone Research (2020) 8:1; https://doi.

Egg and sperm binding and correct recognition is the first stage for successful fertilization. In red algae, spermatial attachment to female trichogynes is mediated by a specific binding between the lectin(s) distributed on the surface of trichogyne and the complementary carbohydrates on the spermatial surface. A female-specific lectin was isolated from Aglaothamnion callophyllidicola by agarose-bound fetuin affinity chromatography. Two proteins, 50 and 14 kDa, eluted from the fetuin column were separated using a native-polyacrylamide gel electrophoresis method and subjected to a gamete binding assay. The 50 kDa protein, which blocked spermatial binding to female trichogynes, was used for further analysis. Internal amino acid sequence of the 50 kDa protein was analyzed using matrix-assisted laser desorption/ionization-mass spectrometry and degenerated primers were designed based on the information. A full-length cDNA encoding the lectin was obtained using rapid amplification of cDNA ends polymerase chain reaction (PCR). The cDNA was 1552 bp in length and coded for a protein of 450 amino acids with a deduced molecular mass of 50.7 kDa, which agreed well with the protein data. Real-time PCR analysis showed that this protein was up-regulated about 10-fold in female thalli. As the protein was novel and showed no significant homology to any known proteins, it was designated Rhodobindin.

Defective aquaporin4 (AQP4)-mediated glymphatic drainage has been linked to tauopathy and amyloid plaque in Alzheimer’s disease. We now show that brain interleukin33 (IL33) is required for regulation of AQP4 expression in astrocytes, especially those at neuron-facing membrane domain (n-AQP4). First, IL33-deficient (Il33−/−) mice showed a loss of n-AQP4 after middle age, which coincided with a rapid accumulation of abnormal tau in neurons and a reduction in drainage of abnormal tau to peripheral tissues. Second, injection of recombinant IL33 induced robust expression of AQP4 at perivascular endfoot (p-AQP4) of astrocytes, but not n-AQP4, in Il33−/− brains. Although the increased p-AQP4 greatly accelerated drainage of intracerebroventricularly injected peptides, it did not substantially accelerate drainage of abnormal tau. These results suggest that p-AQP4 drives overall convective flow toward perivenous space, i.e., glymphatics, whereas n-AQP4 may generate an aqueous flow away from neurons to remove neuronal wastes, e.g., abnormal tau. We have previously shown the role of brain IL33 in DNA repair and autophagy in neurons with oxidative stress. Now, we show that IL33 deficiency also impairs glymphatic drainage. Defects in those mechanisms together may lead to chronic neurodegeneration and tauopathy at old age in IL33-deficient mice.