Clearing Microglia Without Clearing Amyloid Produces Benefits in a Mouse Model of Alzheimer's Disease

Researchers have reduced inflammation and cell death in a mouse model of Alzheimer's disease by reducing the numbers of microglia present in brain tissue, an approach that doesn't reduce amyloid-β levels associated with the progression of Alzheimer's disease even though it results in functional benefits. Microglia are a class of immune cell specific to the brain, where portions of the immune system have more roles and more complicated roles than is the case elsewhere in the body. Types of immune cell only found in the brain are responsible for supporting neurons in many ways, not just by attacking pathogens. Dysfunction in microglia has long been implicated in the chronic inflammation that accompanies many neurodegenerative conditions, and microglia are a target for numerous lines of research related to potential Alzheimer's therapies, which in some cases include increasing microglial activity or otherwise altering their behavior rather than the approach of removal tried here.

Animal models are never the same as the human disease they are trying to mimic, and that can mean garbage in, garbage out. Judging relevance of results must always be on a case by case basis, and while considering all of the fine details, because just as it is possible to learn a great deal from a good animal model, it is also possible to create states and scenarios in that same animal model that have no real relevance to human biochemistry. For example, researchers have in the past created scenarios in which mice are heavily loaded with amyloid-β and yet show few or no signs of neurodegeneration, and it has never been entirely clear as to the degree to which that helps in understanding Alzheimer's disease in humans. This microglia study might help shed some further light on those results, at least in mouse models, given the inflammation angle. It is generally accepted that inflammation is important in the progression of Alzheimer's disease, and there are certainly other studies in mice models in which reductions in inflammation have been shown to reduce Alzheimer's-like symptoms.

On the whole, this study does well as supporting evidence for those who are trying to build treatments for neurodegenerative conditions based on targeting microglia. As is the case for a lot of the work on Alzheimer's in animal models, it raises at least as many questions as it answers, however.

Blocking inflammation prevents cell death, improves memory in Alzheimer's disease

Researchers found that flushing away the abundant inflammatory cells produced in reaction to beta-amyloid plaques restored memory function in test mice. Their study showed that these cells, called microglia, contribute to the neuronal and memory deficits seen in this neurodegenerative disease. "Our findings demonstrate the critical role that inflammation plays in Alzheimer's-related memory and cognitive losses. While we were successful in removing the elevated microglia resulting from beta-amyloid, further research is required to better understand the link among beta-amyloid, inflammation and neurodegeneration in Alzheimer's."

The neurobiologists treated Alzheimer's disease model mice with a small-molecule inhibitor compound called pexidartinib, or PLX3397, which is currently being used in several cancer studies. The inhibitor works by selectively blocking signaling of microglial surface receptors, known as colony-stimulating factor 1 receptors, which are necessary for microglial survival and proliferation in response to various stimuli, including beta-amyloid. This led to a dramatic reduction of these inflammatory cells, allowing for analysis of their role in Alzheimer's. The researchers noted a lack of neuron death and improved memory and cognition in the pexidartinib-treated mice, along with renewed growth of dendritic spines that enable brain neurons to communicate. Although the compound swept away microglia, the beta-amyloid remained, raising new questions about the part these plaques play in Alzheimer's neurodegenerative process.

Eliminating microglia in Alzheimer's mice prevents neuronal loss without modulating amyloid-β pathology

In addition to amyloid-β plaque and tau neurofibrillary tangle deposition, neuroinflammation is considered a key feature of Alzheimer's disease pathology. Inflammation in Alzheimer's disease is characterized by the presence of reactive astrocytes and activated microglia surrounding amyloid plaques, implicating their role in disease pathogenesis. Microglia in the healthy adult mouse depend on colony-stimulating factor 1 receptor (CSF1R) signalling for survival, and pharmacological inhibition of this receptor results in rapid elimination of nearly all of the microglia in the central nervous system.

In this study, we set out to determine if chronically activated microglia in the Alzheimer's disease brain are also dependent on CSF1R signalling, and if so, how these cells contribute to disease pathogenesis. Ten-month-old 5xfAD mice were treated with a selective CSF1R inhibitor for 1 month, resulting in the elimination of ∼80% of microglia. Chronic microglial elimination does not alter amyloid-β levels or plaque load; however, it does rescue dendritic spine loss and prevent neuronal loss in 5xfAD mice, as well as reduce overall neuroinflammation. Importantly, behavioural testing revealed improvements in contextual memory. Collectively, these results demonstrate that microglia contribute to neuronal loss, as well as memory impairments in 5xfAD mice, but do not mediate or protect from amyloid pathology.

Comments

@Lou Pagnucco: My first thought was that methods of activation are not just activating, but also changing behavior in other ways that reduce specifically pro-inflammatory activities. Activation degree doesn't have to directly map to inflammatory response, and immune dsyregulation in general seems to be a growing disconnection between those two.

Posted by: Reason at March 1st, 2016 12:35 PM

I'd still love to see the effect of IgM antibodies against beta-amyloid rather than the IgG antibodies being used by the pharma industry. Could it be that the IgG antibodies clear the amyloid but also stimulate the microglia in a negative way?

Posted by: Jim at March 1st, 2016 7:39 PM

"On the whole, this study does well as supporting evidence for those who are trying to build treatments for neurodegenerative conditions based on targeting microglia."

I have seen unpublished data showing MSCs modulate Microglia and improve Tau Pathology and shrink plaques. This would confirm Reason's comments above.

The same goes for MSCs and atherosclerosis which is on like Alzheimers of the blood as was recently published in a paper this year.

This papers shows a similar modulation of macrophages using MSCs:

http://www.ncbi.nlm.nih.gov/pubmed/25389006

Posted by: Steve H at March 2nd, 2016 7:48 AM

Another recent paper that also indicts microglia, and may point toward a therapy using the adaptive immune system. Key excerpt:

"Critically, it appears that loss of IgG-producing B cells impairs microglial phagocytosis, thereby exacerbating amyloid deposition. Conversely, replacement of IgGs via direct injection or bone marrow transplantation reverses these effects and reduces Aβ pathology."

The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function
http://www.pnas.org/content/113/9/E1316.abstract

Posted by: Lou Pagnucco at March 2nd, 2016 11:45 AM

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