Salk Institute maps 1,000 hidden brain microproteins linked to Alzheimer’s

Scientists at the Salk Institute have assembled the first atlas of microproteins in the human frontal cortex, cataloging over 1,000 previously uncharacterized tiny proteins and uncovering a potential link between one of them and immune cell dysfunction in Alzheimer's disease. The study, published September 14 in Nature Aging, offers researchers a new resource for investigating the molecular underpinnings of neurodegeneration.salk+1

A Thousand New Proteins Hidden in Plain Sight

Microproteins — a smaller class of proteins that have been largely overlooked due to their size — play important but poorly understood roles in health and disease. Using 480 human frontal cortex samples from brains with and without Alzheimer's disease, researchers Brendan Miller and Alan Saghatelian identified 1,067 uncharacterized microproteins, many never previously detected. The team leveraged ShortStop, an AI-powered tool developed in Saghatelian's lab in 2025, to sift through existing transcriptomic and mass spectrometry data for signs of these elusive molecules.salk+1

"We still do not fully understand the molecular mechanisms of healthy aging, and that is especially true for microproteins, which have been inadvertently overlooked for decades," Saghatelian said in a Salk Institute press release. The atlas is publicly available for other researchers to download and use.salk

A Microprotein Tied to Immune Cell Dysfunction

Among the atlas's findings, the Salk team zeroed in on microglia, the brain's resident immune cells, which commonly become dysfunctional with age and in neurodegenerative diseases. The researchers generated their own mass spectrometry data on microglia and discovered that these cells were producing a specific microprotein from a stretch of genetic code that would normally encode a different, larger protein.salk

When the team removed the gene responsible for the microprotein in microglia, the cells' mitochondria became impaired — suggesting the microprotein plays a role in keeping these immune cells functional. Hundreds of the newly discovered microproteins showed different expression levels in Alzheimer's disease brain cells compared to healthy ones, with Alzheimer's cells tending to express more microproteins overall.salk

Expanding the Playbook Against Neurodegeneration

The research drew on samples from the Religious Orders Study/Memory and Aging Project cohort and was funded by the National Institutes of Health and the Clayton Medical Research Foundation. In a separate but related study also published this week in Nature Neuroscience, researchers at the German Center for Neurodegenerative Diseases found that the chromatin protein DAXX helps keep microglia functional by suppressing normally silent genetic elements that can become active with age, driving inflammation and cellular damage.medicalxpress+1

"Every coach has a playbook, and you want as many plays as possible to win the game," Miller said. "For scientists, the game is trying to understand the disease, and the plays are the proteins and microproteins that may or may not be involved in that disease."salk