IL33 and middle-age aging spurt implicated in late-onset Alzheimer’s disease

Written by Francesca Lake

Research resulting from a collaboration between researchers at the School of Dentistry and the Department of Psychiatry and Behavioral Sciences at McGovern School of Medicine (University of Texas Health Science Center at Houston, TX, USA) has changed our understanding of how the brain ages, providing an insight into how we might be able to detect, and possibly treat, late-onset Alzheimer’s disease (AD) decades prior to symptom onset.
Late-onset sporadic AD is responsible for approximately 95% of all AD cases, and occurs after the age of 65. By the time symptoms are apparent a large amount of neurons have already been lost, making the search for early or predictive biomarkers a must. Recent research has linked it to failed repair of DNA damage in aging neurons, yet its cause remains a mystery.

The team had highlighted IL33 as a protein of interest owing to their previous research. “We observed that when we removed IL33, the ovary shrank much faster than normal,” explained Yahuan Lou (McGovern School of Medicine). “So we wondered: If IL33 does this in the ovary, what does it do in the brain? The brain has an abundance of IL33.”

The study utilized mice to demonstrate that aging in neurons suddenly increases around the mouse equivalent of age 40. This resulted in an increase of IL33 in normal mice, a protein that activates neuronal repair mechanisms and that was expressed by up to 75% of aged astrocytes. Mice lacking the gene for IL33 continued to decline, exhibiting tau abnormalities and a loss of neurons in the cerebral cortex and hippocampus. They went on to develop dementia at 60—80 weeks, an age equivalent to approximately 68 in humans.

Commenting on the significance of the work, the authors noted: “If a neuronal aging surge at middle age (45–50 years) exists in humans, it will be then a promising time point to search for biomarkers for early diagnosis of AD long before massive loss of neurons. Our model will be a useful tool in exploring these biomarkers.”

This research also complements recent research examining IL33 in early-onset AD. “When they injected IL33 into the [Alzheimer’s] mice, they saw that the plaque load was reduced, but they didn’t know why,” noted Lou. “We’ve figured out why.”

IL33 injections temporarily relieved symptoms for a period of time equivalent to several months in humans. While not a cure, this highlights potential therapeutic options to investigate, such as finding a way to enhance the brain’s IL33 supply.

Furthermore, IL33 could be a new lead in the continued search for the cause of late-onset AD.

Sources: Carlock C, Wu J, Moreno-Gonzalez I et al. Interleukin33 deficiency causes tau abnormality and neurodegeneration with Alzheimer-like symptoms in aged mice. Transl. Psychiatry 7(7) e1164 (2017);