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Microglia are the brain’s immune cells that clean out debris, such as damaged proteins and old cell parts, to keep the organ healthy. But the very properties that make these cells so useful might also be a driving factor in Alzheimer’s disease. According to a new study published in the journal Nature, microglia may be accidentally destroying vital brain connections as they struggle to deal with backlogs of aging proteins.
Neurodegenerative diseases affect around 1 in 12 people globally, and age is by far the most important risk factor. While much Alzheimer’s research focuses on well-known marker…
Credit: Unsplash/CC0 Public Domain
Microglia are the brain’s immune cells that clean out debris, such as damaged proteins and old cell parts, to keep the organ healthy. But the very properties that make these cells so useful might also be a driving factor in Alzheimer’s disease. According to a new study published in the journal Nature, microglia may be accidentally destroying vital brain connections as they struggle to deal with backlogs of aging proteins.
Neurodegenerative diseases affect around 1 in 12 people globally, and age is by far the most important risk factor. While much Alzheimer’s research focuses on well-known markers like amyloid plaques (sticky protein clumps outside cells) and tau tangles (twisted fibers inside cells), scientists at Stanford University focused on the brain’s system for making and disposing of proteins.
Tracking brain proteins
The researchers wanted to understand what happens when this process fails, which it does in all aging brains. They used healthy aging mice and compared 4-month-old rodents with 24-month-old rodents to see how proteostasis (the brain’s system for maintaining and recycling proteins) breaks down just from aging.
To see what was happening inside these cells, they developed a new tool called BONCAT (Bioorthogonal Non-Canonical Amino Acid Tagging), which enabled them to tag and track newly synthesized proteins. This allowed them to follow the proteins from when they were made to when they eventually failed to be cleared away.
Evaluation of Nascent Protein Labeling by AAV-Based Delivery of PheRS*. Credit: Nature (2026). DOI: 10.1038/s41586-025-09987-9
The scientists discovered that as the brain ages, its ability to recycle proteins collapses. Proteins that used to be cleared out quickly now hang around for twice as long, as the team wrote in their study: "We observed that the half-life of neuronal proteins approximately doubles between young and aged mice, revealing a substantial loss of neuronal proteome maintenance with aging."
This slowdown leads to more than 1,700 proteins clumping together, with the worst clogs occurring at synapses, where brain cells send and receive signals. As these proteins begin to accumulate, the microglia step in to clear the mess.
"Synaptic proteins are highly enriched among those that slow down, aggregate, and ultimately accumulate in microglia, suggesting a cascade from impaired synaptic protein turnover to synapse engulfment."
Self-inflicted damage
The research findings suggest that when a neuron’s recycling system fails, microglia try to clear the damaged proteins. However, because these proteins are inside the brain’s communication hubs, they may end up destroying the hubs themselves.
"The number of age-impaired proteins that accumulate in microglia is significantly more than expected by random chance, indicating that microglia may selectively remove aberrant protein species from neurons to maintain proteostasis—but at the cost of synapse loss," the researchers explain.
If this is indeed a cause of dementia, the discovery could give us a new way to fight it by designing therapeutics that restore this protein recycling system in the brain.
Written for you by our author Paul Arnold, edited by Gaby Clark, and fact-checked and reviewed by Robert Egan—this article is the result of careful human work. We rely on readers like you to keep independent science journalism alive. If this reporting matters to you, please consider a donation (especially monthly). You’ll get an ad-free account as a thank-you.
Publication details
Ian H. Guldner et al, Ageing promotes microglial accumulation of slow-degrading synaptic proteins, Nature (2026). DOI: 10.1038/s41586-025-09987-9
Journal information: Nature
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Citation: The brain’s protein cleanup process may play a role in dementia (2026, January 29) retrieved 29 January 2026 from https://medicalxpress.com/news/2026-01-brain-protein-cleanup-play-role.html
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