Alzheimer's disease (AD) is estimated to be responsible for up to 70% of dementia cases, but after decades of research, the causes remain uncertain. The leading theory is that AD is driven by the accumulation of particular misfolded proteins in the brain: amyloid-beta (a-β) and phosphorylated tau (p-τ). However, there are reasons to believe that this may not be the full story.
A newer theory is that a type of immune cell resident in the brain, known as microglia, could contribute to the pathology associated with AD. These cells normally have a 'janitorial' role, helping to keep the brain clean by mopping up a-β and p-τ, and fighting infections by stimulating an immune response. They also release chemicals, such as brain-derived neurotrophic factor, which promote neuron survival. However, it is thought that if these cells start to malfunction, this could result in the neuron death seen in AD. For example, when microglia are chronically activated by inflammatory stimuli (for example, the a-β and p-τ themselves), they start to lose their ability to get rid of misfolded proteins, causing a vicious cycle where the proteins may accumulate and the microglia continue to lose functionality. As part of their immune role, microglia can also release proinflammatory and potentially neurotoxic chemicals, and chemicals that promote the further accumulation of a-β and p-τ. Therefore, when microglia are chronically activated, they can not only contribute to further accumulation of misfolded proteins, but can actually secrete chemicals that promote neuron death. Could microglia hold the key to the mechanism behind AD?
While this avenue of research is relatively young, methods of treating AD that target microglia are already the subject of patent applications. Some treatments seek to counteract the over-activation of microglia and therefore reduce any toxic effects, or push them towards a less harmful state. For example, US Patent 10,286,093 relates to a method of targeting hyperactive microglia and selectively killing these cells. However, another emerging strategy, such as that employed in US Patent 9,149,492, is to further stimulate microglia to more effectively clear the accumulating proteins. Indeed, the Lukens Lab has shown that inhibiting the SYK pathway in microglia, which inhibits the ability of microglia to clear a-β, worsened AD in a mouse model of AD.
Given the devastating, and prevalent, nature of this disease in our ageing population, any potential means to counter its impact would be welcome. As microglia are also implicated in other diseases, such as multiple sclerosis and Parkinson's disease, successful microglia-targeting therapies would undoubtedly have a wider impact than just AD. We will have to wait to see if targeting microglia could give us the breakthrough we have been waiting for.
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