Highlights •Early neural stem cell NSC impairment in 3xTg-AD mice correlates with SVZ subventricular zone niche lipid accumulations •Similar lipid accumulations are found in the SVZ in postmortem human AD brains •Accumulating SVZ lipids are locally generated, oleic acid-enriched triglycerides •Inhibiting oleic acid signaling or synthesis rescues NSC defects in 3xTg-AD mice Credit: Fernandes et al. Aberrant Lipid Metabolism in the Forebrain Niche Suppresses Adult Neural Stem Cell Proliferation in an Animal Model of Alzheimer’s Disease. Cell Stem Cell, 27 August 2015 DOI: 10.1016/j.stem.2015.08.001
For the 1st time since the disease was described 109 years ago, researchers have discovered accumulations of fat droplets/ lipids in the brain of patients who died from the disease and have identified the nature of the fat. This breakthrough opens up a new avenue in the search for a medication to cure or slow the progression of Alzheimer’s disease.
This study highlights what might prove to be a missing link in the field. Researchers initially tried to understand why the brain’s stem cells, which normally help repair brain damage, are unresponsive in Alzheimer’s disease. Doctoral student Laura Hamilton was astonished to find fat droplets near the stem cells, on the inner surface of the brain in mice predisposed to develop the disease. “We realized that Dr. Alois Alzheimer himself had noted the presence of lipid accumulations in patients’ brains after their death when he first described the disease in 1906. But this observation was dismissed and largely forgotten due to the complexity of lipid biochemistry,” said Laura Hamilton.
The researchers examined the brains of 9 patients who died from Alzheimer’s disease and found significantly more fat droplets compared with five healthy brains. Advanced mass spectrometry technique to identify these fat deposits as triglycerides enriched with oleic acids, also found in animal fats and vegetable oils.
“We discovered that these fatty acids are produced by the brain, that they build up slowly with normal aging, but that the process is accelerated significantly in the presence of genes that predispose to Alzheimer’s disease,” explained Karl Fernandes. In mice predisposed to the disease, we showed that these fatty acids accumulate very early on, at 2 months of age, which corresponds to the early twenties in humans. Therefore, we think that the build-up of fatty acids is not a consequence but rather a cause or accelerator of the disease.”
Fortunately, there are inhibitors of the enzyme that produces these fatty acids. These molecules, which are currently being tested for metabolic diseases such as obesity, could be effective in treating Alzheimer’s disease. “We succeeded in preventing these fatty acids from building up in the brains of mice predisposed to the disease. “This is very promising because stem cells play an important role in learning, memory and regeneration.”
This discovery lends support to the argument that Alzheimer’s disease is a metabolic brain disease, like obesity or diabetes are peripheral metabolic diseases.
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