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Could Research in Mice Change How We Look at Alzheimer Disease?

Fluorescent "flowers" in mouse brains give us a new look at Alzheimer disease. And laboratory mice given a dietary supplement run mazes well.

A study in mice suggests that the usual way neuroscientists look at Alzheimer disease might be wrong. What’s more, recent research suggests that a supplement available without a prescription might offer protection against brain deterioration. Let’s look at the supplement first.

Could a Bodybuilder’s Supplement Save Us from Alzheimer Disease?

Researchers in Chicago have announced a tantalizing finding (Cell Reports, July 11, 2023). Mice engineered to develop a condition that mimics Alzheimer disease can be protected with an over-the-counter supplement. Giving the mice beta-hydroxy-beta-methylbutyrate, also known as HMB, reduced brain plaques and increased neurotrophic proteins that protect neurons. It binds to a nuclear hormone receptor called peroxisome proliferator-activated receptor, or PPARα. Oral HMB helped preserve maze performance in the mice.

We must keep in mind that some strategies that protect mice from cognitive decline do not always work in humans. Nevertheless, this approach is intriguing. HMB is a popular supplement in bodybuilding circles because it helps increase muscle. Bodybuilders taking it have not reported serious side effects. As a result, the investigators suggest that it might be useful in treating people with Alzheimer dementia. To know whether it will work for this, we will need to see a randomized controlled trial in humans.

A New Way to Look at Alzheimer Disease:

Now for the critical question of what actually causes Alzheimer disease. For decades, researchers have identified plaques of amyloid beta as the major feature of Alzheimer’s disease. They believed that amyloid collected outside of cells and caused the classical brain damage associated with this type of dementia. That includes injury to the hippocampus, a brain structure important for retrieving short term memories.

Investigators at New York University discovered, however, that problems with waste disposal inside brain cells could be the source of the destruction (Nature Neuroscience, June 2, 2022). Lysosomes that are supposed to rid neurons of cellular debris fail to operate efficiently. Instead they allow amyloid to start accumulating within the cell.

Poisonous Flowers Under the Microscope:

To get a fresh look at Alzheimer disease progression, the researchers injected mice with fluorescent compounds that accumulated in the brain. The first step is that lysosomes lose some of the acidic enzymes that they use to clean up used proteins and organelles. Consequently, they engulf these obsolete structures but cannot digest them. Eventually, the neurons end up with large membrane blebs full of amyloid beta. When tagged with fluorescent chemical markers, these cluster into structures that resemble flowers. That’s why the investigators have dubbed them PANTHOS (poisonous anthos, which means flower).

Ultimately, the accumulation of beta-amyloid fibrils inside the cells overwhelm them. If you look at Alzheimer disease this way, PANTHOS lead to extracellular beta-amyloid plaque in the brain. When scientists looked for PANTHOS in brains from humans who died of Alzheimer disease, they found very similar structures.

One of the key researchers points out the problems with past studies and drug development:

“This new evidence changes our fundamental understanding of how Alzheimer’s disease progresses; it also explains why so many experimental therapies designed to remove amyloid plaques have failed to stop disease progression, because the brain cells are already crippled before the plaques fully form outside the cell.”

Some Clinicians Want a Different Approach:

In an opinion piece for the website STAT, Dr. Howard Fillit says it is time to take a more diverse approach to understanding and treating dementia. He points out that we need better biomarkers for early diagnosis. These would also help scientists identify high-risk patients to participate in clinical trials. He also urges his colleagues to repurpose drugs already on the market if they can help slow disease progression. For that, though, we will need more studies and a different way to look at Alzheimer disease.

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About the Author
Terry Graedon, PhD, is a medical anthropologist and co-host of The People’s Pharmacy radio show, co-author of The People’s Pharmacy syndicated newspaper columns and numerous books, and co-founder of The People’s Pharmacy website. Terry taught in the Duke University School of Nursing and was an adjunct assistant professor in the Department of Anthropology. She is a Fellow of the Society of Applied Anthropology. Terry is one of the country's leading authorities on the science behind folk remedies..
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  • Paidi RK et al, "Muscle-building supplement β-hydroxy β-methylbutyrate binds to PPARα to improve hippocampal functions in mice." Cell Reports, July 11, 2023. DOI:https://doi.org/10.1016/j.celrep.2023.112717
  • Lee J-H et al, "Faulty autolysosome acidification in Alzheimer’s disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques." Nature Neuroscience, June 2, 2022. https://doi.org/10.1038/s41593-022-01084-8
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