Fat droplets identified in brains of Alzheimer’s patients for the first time.


Over 47.5 million people worldwide have Alzheimer’s disease or some other type of dementia, according to the World Health Organization. Despite decades of research, the only medications currently available treat the symptoms alone.  Now, for the first time since the disease was described 109 years ago, researchers at the University of Montreal have discovered accumulations of fat droplets in the brain of patients who died from the disease and have identified the nature of the fat.  The team states that their new study opens up a new avenue in the search for a medication to cure or slow the progression of Alzheimer’s disease.  The opensource study is published in the journal Cell Stem Cell.

The researchers note that the study highlights what might prove to be a missing link in the field. Previous studies initially tried to understand why the brain’s stem cells, which normally help repair brain damage, are unresponsive in Alzheimer’s disease. The lab state they found fat droplets near the stem cells, on the inner surface of the brain in mice predisposed to develop the disease.  The group 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.  However, the lab state that this observation was dismissed and largely forgotten due to the complexity of lipid biochemistry.

The current study found fatty acid deposits in the brain of patients who died from the disease and in mice that were genetically modified to develop Alzheimer’s disease.  The data findings suggest that these abnormal fat deposits could be a trigger for the disease.  The researchers examined the brains of nine patients who died from Alzheimer’s disease and found significantly more fat droplets compared with five healthy brains. The team then used an advanced mass spectrometry technique to identify these fat deposits as triglycerides enriched with specific fatty acids, which can also be found in animal fats and vegetable oils.

The results showed that these fatty acids are produced by the brain and build up slowly with normal aging.  However, the team explain that the process is accelerated significantly in the presence of genes that predispose to Alzheimer’s disease. In mice predisposed to the disease, data findings show that these fatty acids accumulate very early on, at two months of age, which corresponds to the early twenties in humans. Therefore, the lab hypothesize that the build-up of fatty acids is a cause or accelerator as opposed to a consequence of the disease.

The group note that there are pharmacological inhibitors of the enzyme that produces these fatty acids. The go on to add that these molecules, which are currently being tested for metabolic diseases such as obesity, may be effective in treating Alzheimer’s disease. In the current study the team prevented these fatty acids from building up in the brains of mice predisposed to the disease. The lab conclude that the impact of this treatment on all the aspects of the disease is not yet known, however, it did significantly increased stem cell activity.  The researchers stress that this is very promising because stem cells play an important role in learning, memory and regeneration.

The group surmise that their discovery lends support to the argument that Alzheimer’s disease is a metabolic brain disease, rather like obesity or diabetes are peripheral metabolic diseases.  For the future the lab is continuing their experiments to verify whether this new approach can prevent or delay the problems with memory, learning and depression associated with the disease.

Source:  University of Montreal Hospital Research Centre (CRCHUM)

 

Lipid metabolism is fundamental for brain development and function, but its roles in normal and pathological neural stem cell (NSC) regulation remain largely unexplored. Here, we uncover a fatty acid-mediated mechanism suppressing endogenous NSC activity in Alzheimer’s disease (AD). We found that postmortem AD brains and triple-transgenic Alzheimer’s disease (3xTg-AD) mice accumulate neutral lipids within ependymal cells, the main support cell of the forebrain NSC niche. Mass spectrometry and microarray analyses identified these lipids as oleic acid-enriched triglycerides that originate from niche-derived rather than peripheral lipid metabolism defects. In wild-type mice, locally increasing oleic acid was sufficient to recapitulate the AD-associated ependymal triglyceride phenotype and inhibit NSC proliferation. Moreover, inhibiting the rate-limiting enzyme of oleic acid synthesis rescued proliferative defects in both adult neurogenic niches of 3xTg-AD mice. These studies support a pathogenic mechanism whereby AD-induced perturbation of niche fatty acid metabolism suppresses the homeostatic and regenerative functions of NSCs.  Aberrant Lipid Metabolism in the Forebrain Niche Suppresses Adult Neural Stem Cell Proliferation in an Animal Model of Alzheimer’s Disease.  Fernandes et al 2015.

Lipid metabolism is fundamental for brain development and function, but its roles in normal and pathological neural stem cell (NSC) regulation remain largely unexplored. Here, we uncover a fatty acid-mediated mechanism suppressing endogenous NSC activity in Alzheimer’s disease (AD). We found that postmortem AD brains and triple-transgenic Alzheimer’s disease (3xTg-AD) mice accumulate neutral lipids within ependymal cells, the main support cell of the forebrain NSC niche. Mass spectrometry and microarray analyses identified these lipids as oleic acid-enriched triglycerides that originate from niche-derived rather than peripheral lipid metabolism defects. In wild-type mice, locally increasing oleic acid was sufficient to recapitulate the AD-associated ependymal triglyceride phenotype and inhibit NSC proliferation. Moreover, inhibiting the rate-limiting enzyme of oleic acid synthesis rescued proliferative defects in both adult neurogenic niches of 3xTg-AD mice. These studies support a pathogenic mechanism whereby AD-induced perturbation of niche fatty acid metabolism suppresses the homeostatic and regenerative functions of NSCs. Aberrant Lipid Metabolism in the Forebrain Niche Suppresses Adult Neural Stem Cell Proliferation in an Animal Model of Alzheimer’s Disease. Fernandes et al 2015.

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