In a new study from Scripps Research, researchers used advanced imaging methods to reveal how the production of the Alzheimer’s-associated protein amyloid-beta (Aβ) in the brain is tightly controlled by cholesterol.
They showed that cholesterol is acting essentially as a signal in neurons that determines how much Aβ gets made.
The finding advances understanding of how Alzheimer’s disease develops and underscores the important role of brain cholesterol.
A type of Aβ in the Alzheimer’s brain can form large, insoluble aggregates that gather in extensive clumps or “plaques”—one of the most prominent features of the disease at autopsy.
Genetic evidence correlates the production of a subtype of Aβ with Alzheimer’s, yet Aβ’s role in both the healthy brain and in disease remains a subject of debate.
In the study, the team took a close look at cholesterol’s connection to Aβ production.
They used an advanced microscopy technique called super-resolution imaging to “see,” in cells and in the brains of live mice and tracked how cholesterol regulates Aβ production.
The team focused on cholesterol produced in the brain by essential helper cells called astrocytes, and saw it was carried by apoE proteins to the outer membranes of neurons.
They found that blocking the flow of cholesterol would effectively preventing Aβ production.
When they shut off astrocyte cholesterol production in the mice, Aβ production plummeted to near-normal, and Aβ plaques virtually disappeared.
Another classic Alzheimer’s sign usually seen in these mice is the accumulation of tangled aggregates of a neuronal protein called tau—and those disappeared too.
By confirming and clarifying the role of astrocyte-produced cholesterol in Aβ production, the study suggests that targeting this process has the potential to prevent Alzheimer’s progression.
The team notes, however, that cholesterol is needed by the brain for many other processes, including the maintenance of normal alertness and cognition.
The findings offer new evidence of the underlying factors advancing the development of Alzheimer’s.
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The study is published in the Proceedings of the National Academy of Sciences. One author of the study is Scott Hansen, Ph.D.
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