In an ever-growing, ageing population, neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease are becoming more and more prevalent. Years of research have uncovered many key players in the origin and progression of these diseases, though an effective therapy is still much sought after.
Neurodegenerative diseases have many pathologies and causes that are specific to each type. Alzheimer’s disease is characterized by the accumulation of toxic proteins called Amyloid beta and a reduction in the connections between neurons (called synapses) in the brain. One common aspect present in all neurodegenerative diseases is neuroinflammation, an immune response mediated largely by cells in the brain called microglia. Microglia make up 5-20% of brain cells and play a significant role in disease and injury. They help to ‘clean up’ in the brain removing dead cells and debris to keep the brain functioning healthily. When the brain is under stress or experiences injury, the microglia are activated and release pro inflammatory mediators called cytokines, such as IL-6 and TNF-a, as a protective mechanism. In a healthy brain, the release of these molecules produces local inflammation that signals back to the microglia that they are needed to clear and repair the injury. In chronic neuroinflammation, the constant activation of microglia leads to sustained release of toxic cytokines and an excessive, pathogenic inflammation ensues. Such chronic inflammation of the nervous tissue triggered by persistent injury or toxic protein build up in the brain is detrimental and eventually results in the microglia damaging the neurons.
In Alzheimer’s disease, it was believed that microglia were initially activated as a defensive response, to fight against and remove the toxic build up of Amyloid beta. It is now hypothesized that as the microglia become chronically activated, they not only act on toxic proteins but start to indiscriminately destroy synapses in the brain. It is at this point that microglia activation may become a damaging pathogenic response, leading to the exacerbation and development of Alzheimer’s disease. Excessive microglia activity on synapses is likely to play a crucial role in the loss of cognition and memory.
An alternate theory proposes a ‘yin and yang’ role of microglia in Alzheimer’s disease. This suggests early on in disease states, microglia are helpful and are positively recruited to sites of toxic Amyloid Beta build up. However as the disease progresses the microglia become overwhelmed, and signal this through excessive release of toxic pro-inflammatory cytokines. One study using brain scanners describes a ‘twin peak’ of microglia activation in patients suffering from Alzheimer’s Disease – an early protective peak and a later pro-inflammatory peak (Wood, H. 2017).
Aligned with the ‘yin and yang’ theory, microglia can exist in one of two phenotypes; a pro-inflammatory form, associated with neurotoxicity (M1) and an anti-inflammatory form associated with neuroprotection (M2) (Song, G.J. and Suk, K. 2017). M1 phenotypes produce toxic pro-inflammatory mediators such as TNF-a and IL-6, which activate the cells to deal with infection or injury. After an initial first response of the M1 microglia, M2 phenotypes produce anti-inflammatory cytokines such as IL-10, which lead to brain repair. Chronic exposure to the pro-inflammatory toxic amyloid beta plaques maintains the activation of M1 microglia, which eventually contributes to neuron and synapse damage, leading to neuronal degeneration. Identifying the mechanisms that modulate the M1/M2 phenotypes could help uncover how local CNS inflammation can lead to the devastating effects of neuronal degeneration. Additionally, finding ways to control and reduce this chronic microglia activation and inflammation in Alzheimer’s’ disease could have huge therapeutic benefit. Several pharmacological interventions to modulate the microglial phenotypes have been investigated, however all have had limited efficacy when tested in clinical trials. A better understanding of the mechanisms involved in microglia activation and polarization is needed to go forward.
Possible therapeutic interventions
One avenue currently being explored involves a class of drug called Histone Deacetylase inhibitors (HDACi). Histone deacetylase’s are enzymes that remove acetyl groups from lysine amino acids in proteins and are involved in regulating gene expression within our cells. Research has shown HDAC’s are implicated in inflammatory responses (Kannan, V. 2013), interacting with the microglia in our brains. It is clear that inhibitors of HDAC suppress this microglia-activated immune response and push microglia towards the protective M2 phenotype (Waang, G. 2015), but exactly how they do so is not known.
It was assumed HDAC inhibitors achieve this by increasing gene expression within microglia. However recently published research by neuroscientists at the University of Leeds (Wood, I. 2017) has shown that HDAC inhibitors can still inhibit microglia activation even when the synthesis of new proteins is stopped, suggesting that their ability to increase gene expression is not important for their effect in microglia. Studying where in the cell that the HDACs exert their effects is the first step in identifying the important target protein, and will ultimately lead to uncovering the mechanisms by which they work to push microglia towards the M2 phenotype, hence reducing the inflammatory response.
One problem with using HDAC inhibitors as a therapeutic intervention is that they act in a very broad non-specific fashion, affecting many cell processes. Uncovering how HDAC inhibitors work to reduce M1 microglia activation would allow an opportunity to develop more targeted and specific therapeutic interventions for Alzheimer’s disease with reduced potential for deleterious side effects. Chronic neuroinflammation is a common pathology shared with other neurodegenerative disorders, and thus finding ways to control and reduce microglia activation using HDAC inhibitors will not only be crucial in Alzheimer’s disease, but will be beneficial more widely.
Author: Rachel Coneys
Edited by: Molly Campbell
Wood, H., 2017. Alzheimer disease: Twin peaks of microglial activation observed in Alzheimer disease. Nat Rev Neurol. 13(3):p129
Wood, I., Grigg, R., and Durham, B., 2017. Inhibition of histone deacetylase 1 or 2 reduces microglia activation through a gene expression independent mechanism. Found online at: http://www.biorxiv.org/content/early/2017/02/10/107649
Song, G.J., and Suk, K., 2017. Pharmacological Modulation of Functional Phenotypes of Microglia in Neurodegenerative Diseases. Front Aging Neurosci. 15;9:p139
Kannan, V., Brouwer, N., Hanisch, U.K., Regen, T., Eggen, B.J., and Boddeke, H.W., 2013. Histone deacetylase inhibitors suppress immune activation in primary mouse microglia. J Neurosci Res. 91(9):p1133-42
Wang, G., Shi, Y., Jiang, X., Leak, R. K., Hu, X., Wu, Y., and Chen, J., 2015. HDAC inhibition prevents white matter injury by modulating microglia/macrophage polarization through the GSK3β/PTEN/Akt axis. Proceedings of the National Academy of Sciences, 112(9), 2853-2853.