CSI: Alzheimer’s — Part 2: Beyond Amyloid and Tau

*This is part of UF Explore magazine’s CSI: Alzheimer’s. Click here to read the full story or listen above.

Click here to read part 1.

By Michelle Koidin Jaffee

Among those looking at Alzheimer’s from a different perspective is Malú Gámez Tansey, a prominent neuroscientist recruited to UF from Emory University in 2019 through the founding gift for the Norman Fixel Institute.

Tansey’s research focuses on the roles of inflammation and the immune system in the development and progression of neurodegenerative diseases, including Alzheimer’s. As humans age, she explains, our immune systems are less efficient and more vulnerable to potential exposures, leading in some cases to chronic inflammation as toxic proteins accumulate and aren’t cleared from neurons.

“We believe that could be a result of aging, sluggish or nonfunctional immune cells,” says Tansey, co-director of the Center for Translational Research in Neurodegenerative Disease. “The vacuum cleaners of the brain, the vacuum cleaners of your organs that keep the house tidy, become less competent as you get older.”

Meaning, she says, amyloid buildup could be a consequence, rather than a cause, of Alzheimer’s.

Tansey believes Alzheimer’s and other dementias are influenced by both genetics and environment, including variables such as diet, physical exercise, quality and quantity of sleep, and exposure to pesticides and pathogens. “We know that a small percentage of cases for Alzheimer’s and related dementias are strictly genetic — maybe 5 to 10%,” she says.

doctor Tansey describing her research in the lab
Dr. Malú Gámez Tansey
two x-ray images of brain slices: the left brain is primarily calm blues and green shades; meanwhile the brain on the right is lit with blues. greens, reds and oranges in infected areas
Scan of a healthy brain (left) compared to a diseased brain.

In one line of research in her lab, a high-fat, high-sugar diet resulted in an acceleration of amyloid buildup and immune dysfunction in mice genetically engineered for Alzheimer’s pathology.

“The high-fat, high-fructose diet made everything worse,” Tansey says. “It accelerated the whole timeline, which suggests that yes, having chronic inflammation in a setting where you are genetically predisposed is a bad thing.”

Her lab then tested an experimental drug on mice on a high-fat, high-fructose diet or a control diet. The drug, XPro1595, is designed to reduce neuroinflammation. By selectively inhibiting an inflammation-causing protein called soluble tumor necrosis factor, or soluble TNF, in the gut and brain, the drug “was able to reverse some of those changes in the stool microbiome,” she says, referring to changes in bacteria and other microorganisms of the gut. “We thought this was super interesting and may be important.”

It is a critical step showing that some immune system-targeted interventions have the potential to mitigate inflammation and prevent worsening, even when genetic predisposition increases risk, Tansey says.

XPro1595, or pegipanermin, was co-invented by Tansey before coming to UF, and it has been tested in a small, early clinical trial in Australia led by the biotech company INmune Bio.  The trial is partially funded by a “Part the Cloud” award from the Alzheimer’s Association. In the trial, the drug lowered brain inflammation, decreased nerve cell death and improved synaptic function. The trial did not evaluate cognition. The next step will be a double-blind, multisite Phase 2 trial to determine if control of neuroinflammation could have an impact on cognition.

Tansey is a co-inventor on the XPro1595 patent and is a consultant to and has stock ownership in INmune Bio, which has licensed XPro1595 for neurological indications.

Read Part 3: Superagers