Nanomaterial That Mimics Protein Behavior Could Help Treat Alzheimer’s

A new nanomaterial that mimics the behavior of brain proteins could be used as an effective tool to treat Alzheimer's and other neurodegenerative diseases.

The nanomaterial, a “protein-like polymer” or PLP, works by altering the interaction between two key proteins in brain cells that are believed to play a role in the development of diseases like Alzheimer’s, Parkinson’s and amyotrophic lateral sclerosis, or ALS.

The research – a collaboration between researchers at the University of Wisconsin–Madison and nanomaterial engineers at Northwestern University – was published in Advanced Materials.

Targeting brain proteins with nanoscience

The first protein of interest is Nrf2, a transcription factor that helps to regulate cells' defenses against toxic and oxidative threats. It is Nrf2’s strong antioxidant effect that is of the most interest, as this oxidative stress is the common denominator for the neuronal cell loss seen in different neurodegenerative diseases.

Previously, researchers have found evidence suggesting that Nrf2 might be a good target for treating neurodegenerative diseases. In 2022, a group led by Jeffrey Johnson, a professor at the University of Wisconsin–Madison School of Pharmacy, found that increasing Nrf2 activity within astrocytes – a specific type of cell found in the brain – can reduce memory loss in mouse models of Alzheimer’s.

Unfortunately for researchers, translating this insight into something that might be useful for humans has so far remained elusive.

“It’s hard to get drugs into the brain, but it’s also been very hard to find drugs that activate Nrf2 without a lot of off-target effects,” explained Johnson, who is also a corresponding author on the new research paper.

To get around this issue, scientists are now beginning to investigate the potential for nanomaterials to be used to activate Nrf2, instead of drugs.

Nathan Gianneschi, a professor of chemistry at Northwestern University and faculty member at the university’s International Institute for Nanotechnology, is one of the researchers spearheading this research avenue. Gianneschi and his colleagues have previously reported the development of several PLPs, all designed to target different proteins.

Recently, Gianneschi’s group has created a PLP designed to alter the interaction between Nrf2 and another key protein, Keap1, that controls when Nrf2 responds to oxidative stress. The two are bound together in unstressed conditions, with Keap1 releasing Nrf2 to act as an antioxidant when needed.

Using biomaterials to combat oxidative stress

Now, Gianneschi and the University of Wisconsin-Madison researchers – led by Jeffrey Johnson and his wife, senior scientist Dr. Delina Johnson – have teamed up, bringing together Gianneschi’s knowledge of nanomaterials with the Johnsons’ experience investigating mouse model brain cells and neurodegenerative disorders.

In the new study, they found that Gianneschi’s new PLP nanomaterial was extremely effective at binding to Keap1 in primary cortical cultures, allowing Nrf2 to accumulate in the cells’ nuclei and exert its antioxidant effects. Crucially, the PLP did this without causing any of the undesirable off-target effects that have plagued other treatment strategies.

Following the success of the PLP material in cultured cells, the Gianneschi and Johnsons’ groups intend to investigate whether this new nanomaterial could also prove effective in mouse models of neurodegenerative diseases.

“We don’t have the expertise in biomaterials,” said Dr. Delinda Johnson, a senior scientist within the UW-Madison School of Pharmacy. “So getting that from Northwestern and then moving forward on the biological side here at UW shows that these types of collaborations are really important.”

Reference: Carrow KP, Hamilton HL, Hopps MP, et al. Inhibiting the Keap1/Nrf2 protein‐protein interaction with protein‐like polymers. Adv Mater. 2024:2311467. doi: 10.1002/adma.202311467

This article is a rework of a press release issued by the University of Wisconsin-Madison. Material has been edited for length and content.