Researchers at the Medical College of Georgia at Augusta University are looking for a better way to understand why many men with prostate cancer develop Alzheimer’s disease, and whether it is standard hormone therapy treatment or an overactive immune response that is actually contributing to the problem.
The hormone therapy, androgen deprivation therapy, known as ADT, treats the cancer by reducing testosterone, which the cancer needs to grow. But androgen is a key regulator of amyloid metabolism, and when it is removed from the equation, more amyloid is left to form the plaques that are a hallmark of Alzheimer’s disease.
We know that prostate cancer itself largely affects men over 65, a population already at higher risk for Alzheimer’s simply because of their age. What is not yet largely understood is the role ADT may play in the context of cancer and Alzheimer’s disease.”
Qin Wang, MD/PhD, Georgia Research Alliance Eminent Scholar in Neurodegeneration and Inaugural Director of the Program for Alzheimer’s Therapeutic Discovery at MCG
Wang and her research team suspected that the body’s overactive immune response and resulting inflammation may play a role.
To better understand this, they created an animal model of Alzheimer’s disease and cancer, and then performed ADT for eight weeks while monitoring androgen levels and tumor size. “We first wanted to validate our model and also check whether there were cognitive deficits in that group,” Wang said.
They also developed other animal models. A so-called wild type (without Alzheimer’s disease or cancer), a group with only Alzheimer’s disease and a group with only cancer that received ADT therapy – helped the team to further map this complex interplay. The researchers also regularly monitored changes in the blood looking for immune markers.
After eight weeks, they also looked for increased amyloid in the brain, but “to our surprise, we didn’t actually see a significant difference in plaque burden in either group.”
However, they observed a high level of reactivity in the glial cells of the cancer-only groups and the groups treated with ADT. Glial cells are part of the central nervous system and generally support nerve cells, allowing them to function properly. Their hyperactivity is a key indicator of inflammation in the brain, Wang said.
They also noted an increase in pro-inflammatory cytokines, small proteins that cause an increase in inflammation throughout the body, and a decrease in anti-inflammatory cytokines, especially in the animals with Alzheimer’s disease and cancer that received ADT.
The team also looked at the animals’ blood-brain barrier and found that the same group suffered significant damage. Under normal circumstances, this barrier protects the brain against harmful substances, while essential molecules can pass through. “That would explain why there is so much more inflammation in that group,” Wang and team reported in the journal Scientific progress. ‘The ADT treatment actually makes the blood-brain barrier more permeable. Then these immune cells, which are circulating in greater quantities due to the cancer and subsequent treatment, can invade the brain – we call this immune cell infiltration – and cause inflammation, which is associated with cognitive decline.”
To intervene and stop the infiltration of immune cells, Wang and her team turned to a drug already on the market for the treatment of multiple sclerosis and Chron’s disease. Natalizumab is a disease-modifying therapy that works by attaching to immune cells and preventing them from crossing the blood-brain barrier and entering the central nervous system.
Treating the mice that had cancer and Alzheimer’s disease and cancer with a combination of ADT and natalizumab not only reduced infiltration but subsequently improved the integrity of the blood-brain barrier.
“Then we looked at inflammatory markers and those levels were reduced as well,” Wang said. “We’ve essentially reduced the pro-inflammatory cycle and improved cognitive function. We now know it’s not just the amyloid plaques. The immune system response is the contributing factor here.”
Because the drug is already on the market, next steps could include a clinical trial in patients undergoing ADT for prostate cancer.
In addition to Wang, the research team included AU graduate Mae Aida; Shalini Saggu, PhD, assistant professor in the Department of Neuroscience and Regenerative Medicine; Chao Zhang, MD/PhD, who studies cancer and inflammation at the University of Alabama at Birmingham; and Lizhong Wang, MD/PhD, professor in the Department of Genetics and the Comprehensive Cancer Center at UAB.
This work was supported by funding from the National Institute on Aging.
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Magazine reference:
Zhang, C., et al. (2024) Androgen deprivation therapy exacerbates Alzheimer’s-associated cognitive decline via increased infiltration of immune cells in the brain. Scientific progress. doi.org/10.1126/sciadv.adn8709.