New research from UT Health San Antonio, in collaboration with UC Irvine, has revealed that changes in brain lipids play a major role in the development and progression of Alzheimer’s disease. The study shows that lipid imbalances affect how amyloid proteins accumulate, and that genes involved in lipid regulation are tied to Alzheimer’s risk. “The brain is unique,” said Juan Pablo Palavicini, PhD, co-lead author. “Unlike other organs dominated by protein, over half of the brain’s dry weight is made of lipids. In Alzheimer’s, these lipids are severely disrupted, yet most research focuses mainly on genes and proteins.”

Published on Oct. 15 in Nature Communications, the study highlights how microglia the brain’s immune cells shape many of these lipid changes. Depending on how they are altered, microglia can either stabilize lipid balance or worsen disease. The work was led by Palavicini and Xianlin Han, PhD, of the Barshop Institute for Longevity and Aging Studies.

Testing microglia’s role

Using a mouse model of Alzheimer’s, researchers tested two ways to eliminate microglia: through a drug that removed nearly all microglia and through genetically engineered mice lacking microglia. These approaches allowed them to pinpoint which lipid changes were driven specifically by microglia.

They compared mouse findings with human post-mortem brain samples and found that amyloid buildup greatly reshaped lipid patterns. Two lipid groups were especially affected:

Lysophospholipids (LPC and LPE), linked to inflammation and oxidative stress

Bis(monoacylglycero)phosphate (BMP), which regulates lysosomal recycling

A form of BMP containing arachidonic acid (AA-BMP) accumulated around amyloid plaques. Long-term microglia removal prevented this buildup, showing that microglia directly contribute to AA-BMP changes.

Progranulin’s role

The protein progranulin produced by microglia and neurons was identified as a key regulator of lipid balance. Progranulin levels increase in Alzheimer’s and strongly correlate with AA-BMP accumulation. Removing microglia lowered both progranulin and AA-BMP, suggesting that microglial progranulin helps maintain BMP levels and neuronal health.

Influence of other brain cells

Not all lipid disruptions came from microglia. LPC and LPE were regulated mostly by astrocytes and neurons. LPC rose with astrocyte activation, while LPE increased due to oxidative stress and weakened antioxidant systems.

Microglia protect neurons and myelin

The team also found that microglia help maintain myelin, the protective coating on neurons. Removing microglia under amyloid stress reduced myelin-related lipids and increased oxidative stress in neurons, showing that microglia play a protective role in brain lipid metabolism.

A more complete understanding of Alzheimer’s

Overall, the findings show that Alzheimer’s involves far more than amyloid plaques and tau tangles it also includes widespread disturbances in brain lipid regulation. Microglia, astrocytes, and neurons each control different lipid pathways, shaping inflammation, oxidative stress, and cellular recycling.

“Knowing which cells control which lipids gives us new therapeutic targets,” Palavicini said. “By restoring lipid balance alongside targeting amyloid and tau, we can develop more precise and effective strategies to protect neurons and slow or prevent Alzheimer’s disease.”

Source: https://news.uthscsa.edu/targeting-brain-immune-cells-could-restore-alzheimers-related-lipid-imbalance-ut-health-san-antonio-research-shows/