New study links impaired lipid clearance in the brain to Alzheimer’s disease

A study recently published in Nature Metabolism uncovered the role of disrupted brain lipid metabolism in the onset and progression of Alzheimer’s disease. The research was led by researchers at the University of Arizona Health Sciences Center for Innovation in Brain Science and partially funded by the National Institute on Aging.

Alzheimer’s disease is a devastating neurodegenerative disorder characterized by a gradual loss of memory and cognitive function. An estimated 6.5 million Americans aged 65 and older are affected by Alzheimer’s, and this number is projected to increase to 13.9 million by 2060, according to a recent report by the Centers for Disease Control and Prevention. Despite decades of research efforts, there is still a lack of cures for Alzheimer’s, largely due to the unclear mechanisms of the disease.

The paper, co-first authored by Yashi Mi, PhD, and Guoyuan Qi, PhD, revealed that metabolically deficient astrocytes – specialized cells that support and nourish neurons in the brain – cause neuroinflammation and neurodegeneration. The research was led by senior author Fei Yin, PhD, assistant director of translational neuroscience at the Center for Innovation in Brain Science and assistant professor of pharmacology in the College of Medicine – Tucson.

“Our study provides new evidence that compromised removal of lipid waste by the mitochondria in astrocytes is sufficient to trigger lipid accumulation in the brain and to transform astrocytes to be pro-inflammation and neurotoxic, all of which are well-established molecular and cellular hallmarks of Alzheimer’s,” said Dr. Yin, an Arizona Alzheimer’s Disease Research Center Scholar funded by the National Institute on Aging.

Abnormal accumulation of lipids was described in the very first report of Alzheimer’s by Alois Alzheimer, MD, in 1907, and a variety of Alzheimer’s risk factors have been found to be involved in lipid metabolism in the recent decades. However, despite abundant correlational evidence, the mechanisms by which brain lipid accumulation is triggered and how it subsequently contributes to Alzheimer’s disease was not understood.

In an earlier study by Dr. Yin’s group, it was found that the APOE4 gene – the greatest risk factor of Alzheimer's disease – suppresses lipid degradation by astrocytes, which prompted the team to investigate whether impaired clearance of lipids underlies lipid accumulation and neurodegeneration in Alzheimer’s brains.

“Dr. Yin and his team continue to significantly advance our fundamental understanding of the mechanisms driving Alzheimer’s disease,” said Center for Innovation in Brain Science Director Roberta Diaz Brinton, PhD. "From a translational therapeutic perspective, his discoveries create a foundation for precision medicine to restore lipid metabolism in brain and thereby reduce a driver of Alzheimer’s disease pathology.”

In this study, the researchers found that mice with dysfunctional mitochondria, the energy hubs of cells, in astrocytes develop progressive memory impairment, disrupted synaptic transmission and loss of white matter structure that replicate clinical and pathological features of Alzheimer’s.

The team further demonstrated that impaired lipid clearance by mitochondria in astrocytes is an early event prior to cognitive deficits in a mouse model of Alzheimer’s.
 
“Collectively, our results reveal a lipid-centric, Alzheimer’s disease-resembling mechanism by which metabolic deficits in astrocytes progressively induces neurodegeneration. By understanding the role of astrocytes in maintaining brain lipid balance and altering disease progression, we are currently developing new Alzheimer’s therapeutics by restoring the ability of astrocytes to efficiently eliminate excessive lipids from the brain,” Dr. Yin said.

This work was supported in part by National Institute on Aging, a division of the National Institutes of Health, under award numbers RF1AG068175 and P01AG026572; an Arizona Alzheimer’s Consortium Pilot Project grant; and The Packer Wentz Endowment, a private fund that supports research, medical and scientific education.