Interleukin33 deficiency causes tau abnormality and neurodegeneration with Alzheimer-like symptoms in aged mice

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.

The role of Interleukin-33 in patients with mild cognitive impairment and Alzheimer’s disease

“…The aMCI and AD patients lacking IL-33 expression revealed signi cantly cognitive decline, while the patients with IL-33 expression preserved their cognitive function over 1-year period. This nding was consistent with the bidirectional relationship between IL-33 de ciency and neurodegeneration in several studies, including : (1) mice lacking IL-33 had persistent in ammation and severe neurodegeneration in retinal detachment [30]; (2) IL-33 de ciency mice failed to repair deoxyribonucleic acid damage of aged neuron, resulting in neurodegeneration and tau abnormality [19]; (3) mice lacking IL-33 were found to have impaired recovery after CNS injury [16]; and (4) IL-33 treatment rescued contextual memory de cits in AD mouse models [18]. Collectively, our study provided the rst human evidence that linking IL-33 to neurodegeneration in the aMCI and AD patients.…”

“…The CNS has the highest levels of IL-33 expression in all human organs [15][16][17], and recent basic and preclinical studies have reported its extend physiological and pathophysiological role in CNS development [17,19], recovery [16,28,29], and disease [15,18,21]. Here we further our understanding of the IL-33 in human AD research.…”

“…An animal study showed that peripheral IL-33 administration reduced soluble Aβ levels and amyloid plaque deposition and reversed synaptic plasticity impairment and cognitive decline in AD mouse models [18]. Another animal study reported that IL-33 de ciency caused tau abnormality, neurodegeneration, and AD-like symptoms in aged mice [19].…”

A novel Ataxin-3 knock-in mouse model mimics the human SCA3 disease phenotype including neuropathological, behavioral, and transcriptional abnormalities

“…In addition to this, Il33 shows highest expression levels in the central nervous system, being constitutively expressed in astrocytes, microglia, and oligodendrocytes (Liew et al 2016). Moreover, a deficiency for Il33 is associated with neurodegeneration and impaired repair of neurons in aged mice accompanied by memory loss and cognitive impairment, resembling an Alzheimer's disease-like phenotype, including tau abnormality (Carlock et al 2017).…”

Expression and Function of IL-33/ST2 Axis in the Central Nervous System Under Normal and Diseased Conditions

“…Despite suggestions from Wicher et al that IL-33 is only expressed in CNS during late embryogenesis and becoming absent in adult brain ( 17 ), others show that its expression is increased during postnatal development ( 16 , 18 ). IL-33 is also constitutively highly expressed in adult CNS tissues in both human and mouse ( 13 , 16 , 19 , 20 ).…”