Abnormal Lipid Metabolism Suppresses Adult Neural Stem Cell Proliferation in an Animal Model of Alzheimer’s Disease


The brain is deeply dependent on lipid (fatty molecule) metabolism for proper development and function. Could abnormal lipid metabolism affect the brain’s stem cell population? Oh yes.

Karl J.L. Fernandez and his coworkers from the Research Center of the University of Montreal Hospital in Montreal, Canada and other collaborators has shown that neural stem cell populations in the brain can be compromised by abnormal lipid metabolism and that such abnormalities are characteristic of Alzheimer’s disease.

3xTg-AD mice form plaques in their brains that are similar to those in the brains of Alzheimer’s disease patients. Fernandez and his colleagues discovered that 3xTg-AD mice accumulate lipids within ependymal cells, which line the ventricles of the brain and serve as the main support cell of the forebrain Neural Stem Cells (NSCs). Interestingly, brains from Alzheimer’s disease patients, when examined after death also showed the accumulation of lipids within the same cell population.

Fernandes_graphicalabstact

When these lipids were examined further, it was clear that they were oleic acid-enriched fats (oleic acid is found in olive oil). In fact, injecting oleic acid into this area of the brain could recapitulate this pathology. When Fernandez and others inhibited oleic acid synthesis, they were able to fix the stem cell issues in the 3xTg-AD mice.

This fascinating study shows that the pathology in Alzheimer’s disease might be caused by perturbation of fatty acid metabolism in the stem cell niche that suppresses the regenerative functions of NSCs. Preventing accumulation of these fats in the cells surrounding the NSC population can potentially fix the stem cell abnormalities in patients with Alzheimer’s disease.

This study was published in the journal Cell Stem Cell.

Genetically Modified As a Potential Treatment of Alzheimer’s Disease


A neurobiology team from UC Irvine (full disclosure, my alma mater) has used genetically engineered neural stem cells to treat mice with a form of Alzheimer’s disease (AD). Such implanted neural stem cells ameliorated some of the symptoms and pathological consequences of this disease in affected mice.

Patients with AD show accumulation of the protein amyloid-beta in their brains. These amyloid-beta clusters form clear plaques in the brain that are also quite toxic to nearby neurons.

Amyloid beta plaques can be cleared with the protein in them is degraded. Fortunately, the enzyme neprilysin can degrade these plaques, but the brains of AD patients show low levels of this enzyme. Neprilysin levels decrease with age and this is probably one of the reasons AD tends to be a disease of the aged.

The UC Irvine group, under the direction of Mathew Blurton-Jones, tried to deliver neprilysin to the brains of afflicted mice and used neural stem cells to do it. The goal of this work was to determine if increased degradation of the amyloid plaques abated the pathological effects of AD.

In this work, two different AD model systems were used. Thy1-APP and 3xTg-AD mice both exhibit many of the pathological effects of AD, and both were used in this study. Neural stem cells were transfected in express 25 times more neprilysin that normal. Then these genetically modified neural stem cells were transplanted into two areas of the brain known to be affected by AD: the hippocampus and the subiculum, which lies just below the hippocampus. Other AD mice were transplanted with neural stem cells that had not been transformed with neprilysin.

Post-mortem examination of both groups of mice even up to three months after transfection of the neural stem cells showed that those mice that received injections of neprilysin-expressing neural stem cells had significant reductions in amyloid-beta plaques within their brains compared to control mice. The neprilysin-expressing cells even seemed to promote the growth of neurons and the establishment of connections between them.

A truly remarkable finding of this work was that numbers of amyloid-beta plaques were also reduced in area of the brain that were some distance from the areas where the stem cells were injected. This suggests that the injected stem cells migrates across the brain, reducing plaque formation as they went.

Future experiments will seek to see if the reduction in amyloid-beta plaques also leads to improvements in cognition. Also, before this protocol can make its transition from animal models of human trials, the UC Irvine group will need to determine if the neprilysin also degrades soluble forms of amyloid-beta.

Every AD mouse model varies as to the types of pathologies observed in the brains of the affected mice. For this reason, this group tested their treatment strategy in two distinct AD mouse models, and in both cases, the neprilysin-expressing neural stem cells reduced the incidence of amyloid beta plaques. This strengthens the conclusion and neprilysin-expressing neural stem cells can indeed degrade amyloid-beta plaques.

More work needs to be done before this work can be used to support a human trial, but this is certainly an encouraging start to something great.

Brain Cell Regeneration Might Improve Alzheimer’s Disease Symptoms


Adi Shruster and Daniel Offen from Tel Aviv University in Israel have shown in a rodent model of Alzheimer’s disease (AD) that stimulating brain cell regeneration can alleviate some of the symptoms of AD.

A particular mouse strain called 3xTgAD serves as a model system for the study of AD. These mice have several genetic modifications that cause the formation of senile plaques in the brain that also lead to behavioral abnormalities and cognitive decline. In short, the Presenilin gene, which plays a definitive role in the onset of AD, has a mutation engineered in it. This particular mutation (M146V) shows a very strong causative link to inherited forms of AD (MA Riudavets, et al., Brain Pathology 2013 23(5): 595–600).

APP+PS1+Notch

 

Additionally, 3xTgAD mice have a synthetic gene inserted in them that overproduces two proteins that also contribute to the onset of AD: amyloid precursor protein (APP) and another protein called tau. The combination of these three genes causes the formation of amyloid plaques and neurofibrillary tangles that are so characteristic of AD, although these plaques are not exactly the same as those observed in human AD patients (see Matthew J. Winton, et al., Journal of Neuroscience 31(21):7691–7699).

Beta_amyloid

Shruster and Offen used these 3XTgAD mice to determine if inducing new brain cells in the brain could improve their condition. Offen overexpressed a gene called Wnt3a in a part of the brain known to play a role in regulating behavior. Wnt3a is known to drive cell proliferation in this part of the brain. After driving Wnt3a expression in the brains of 3XTgAD mice, Offen subjected them to behavioral tests.

Normal mice tend to pause and assess their surroundings when they enter unfamiliar places. However, 3xTgAD mice tend to charge straight in when entering new surroundings. This lack of proper danger assessment in 3xTgAD mice disappeared when Wnt3a was expressed in their brains. Upon post-mortem examination, these mice showed the formation of new nerve cells in their brains. When new brain cell formation was abrogated with X-rays, the behavioral defect was maintained.

Offen commented: “Until 15 years ago, the common belief was that you were born with a finite number of neurons. You would lose them as you age or as a result of injury or disease.”

Human AD patients can lose their sense of space and reality and do very inappropriate things at particular times. Therefore, these mice do recapitulate particular features of the human disease.

Offen and his colleagues think that establishing the growth of new brain cells in human AD patients might alleviate some of the behavioral abnormalities. Furthermore, stem cell treatments might also have a positive role to play in the treatment of AD, although Offen will readily admit that more work must be done.