by Gizem Terzioglu
figures by MJ Park

Alzheimer’s disease is a progressive neurodegenerative disorder that affects millions of people worldwide, and despite years of research efforts, there is still no cure. However, recent studies have highlighted the crucial roles of microglia, the resident immune cells of our brain, in the development and progression of Alzheimer’s disease. But the question remains: do microglia defend our brain against the disease, or do they contribute to the pathology? The answer is complicated – while microglia normally play critical roles to keep our brain healthy, they may become dysregulated, and their activities may contribute to the development and progression of this debilitating condition. Could these tiny cells be the key to unlocking a cure for Alzheimer’s? 

Alzheimer’s disease 

Alzheimer’s disease is the most common form of dementia. It begins with progressive memory loss and eventually leads to loss of many cognitive abilities. 6.7 million people, or 1 in 9 adults aged 65 or older, are living with Alzheimer’s dementia in the United States as of 2023. A prominent brain pathology associated with Alzheimer’s disease is the build-up of amyloid plaques, which are deposits of a protein called amyloid beta that accumulate between neurons. These plaques can be toxic and disrupt communication between neurons, leading to loss of memory and other cognitive functions. Another common brain pathology observed in Alzheimer’s disease is the neurofibrillary tangles made up of the abnormal accumulation of a protein called tau inside neurons. These tangles disrupt the normal functioning of neurons and hinder the transport of nutrients and other important substances within neurons (Figure 1).

Figure 1. In Alzheimer’s disease, plaques and tangles are two characteristic pathologies found in the brain. Plaques are formed by the accumulation of amyloid beta protein, while tangles result from the twisted fibers of tau protein. These protein aggregates disrupt neuronal communication and contribute to the progressive neurodegeneration and cognitive decline seen in Alzheimer’s disease.

Currently, Leqembi and Aduhelm are the only drugs approved by the U.S. Food and Drug Administration (FDA) for the treatment of Alzheimer’s disease. They are far from a cure for Alzheimer’s and do not stop or reverse the disease, but have been shown to slow down the disease progression to a modest extent. Both drugs are antibodies directed against amyloid beta, and their binding to amyloid beta promotes removal of the plaques from the brain with help from the immune system, including the brain’s immune cells – the microglia

What do microglia do in the brain?

Microglia have numerous functions in the brain, as previously highlighted in the blog. One important function is their ability to phagocytose (a Greek word meaning “eating by a cell”) (Figure 2). Microglia can phagocytose germs, like bacteria and viruses, dead cells, and other potentially harmful particles. Once ingested, these particles normally get digested within the microglia. This allows microglia to clean up the brain environment, so that other cells can continue functioning normally. Foreign particles or other dangerous threats can trigger microglial inflammation, during which microglia release pro-inflammatory molecules to fight off the threat. In certain disease contexts, including Alzheimer’s disease, microglial inflammation can get out of control and damage healthy neurons. Moreover, during development, microglia prune points of contact between neurons, called synapses, in order to eliminate unnecessary connections between neurons and ensure proper organization of brain circuits. While synaptic pruning occurs largely in early development, it may continue into early adulthood in certain brain regions. In Alzheimer’s disease, however, microglial pruning of synapses becomes excessive, which can promote neurodegeneration.

Figure 2. One of the important functions of microglia is phagocytosis, through which microglia can engulf germs, dead or dying cells, cell debris and other harmful particles. Microglia can also prune synapses through phagocytosis. Some of these phagocytosis targets, including dying cells and synapses of healthy neurons, display an “eat-me” signal that microglia can recognize.

In addition to these roles in health and disease, microglia can directly interact with both the amyloid beta that makes up the plaques and the tau protein that makes up the neurofibrillary tangles in an Alzheimer’s brain. Therefore, understanding how microglia interact with amyloid beta and tau may be critical for effectively harnessing these cells to mitigate Alzheimer’s pathology.  

How do microglia interact with the plaques and tangles? 

The question of whether microglia are the underappreciated heroes or the underrated enemies in Alzheimer’s disease continues to puzzle the field (Figure 3). On one hand, microglia can form a physical barrier around the plaques and can phagocytose amyloid beta, which is thought to be useful for both curbing the toxic effects of the plaques and clearing them from the brain environment. However, this helpful function may turn into a harmful one. A 2021 study published in Nature Neuroscience showed that microglia may be carrying around the amyloid beta they engulfed and expelling it into different regions of the brain, propagating the spread of plaques. But this “harmful” function might have an upside after all, as microglia were recently hypothesized to compact the structure of the plaques they have taken up before releasing them, which may reduce the toxic effects of the plaques on neurons. 

Microglia can also interact with the tau protein in several ways. First, microglia can eat any neurons that contain neurofibrillary tangles. Secondly, microglia can uptake any tau that neurons have released into the extracellular environment. However, while microglia may be able to degrade tau, which is beneficial, they may also release tau aggregates into the environment. These tau aggregates can act as seeds to propagate tau pathology, as suggested by a 2021 study published in Science Advances. Tau protein that accumulates outside the cells can be toxic to neurons.

Figure 3. Microglia perform beneficial functions in the healthy brain, and while some of these functions can protect the brain in a disease context, some may also contribute to disease. 1) Microglia form a barrier around plaques and ingest amyloid beta, but may also travel to other parts of the brain and expel the amyloid beta they previously ingested. 2) Microglia can also ingest neurofibrillary tangles that contain aggregated tau protein, but may also release these tau aggregates into the environment, which spreads disease pathology. 3) Microglia contribute to brain circuit organization by pruning synapses during development into early adulthood. In Alzheimer’s disease, microglial pruning of synapses becomes excessive. 4) Another beneficial function of microglia is releasing pro-inflammatory signals during infection to fight off the threat. However, pathological protein deposits can induce excessive release of pro-inflammatory molecules by microglia, which can harm the brain. 

Given that plaques and tangles remain big components of Alzheimer’s disease pathology, microglia are clearly not successful in completely getting rid of them or reducing their toxicity. Microglia may even become harmful to the brain by spreading the pathology, contributing to neurodegeneration by destroying neurons and/or their synapses and promoting inflammation. 

So, should potential treatments reinforce or prevent the activities of microglia? The prevalent approach in the field is trying to take advantage of the beneficial functions of microglia, while suppressing functions that may become harmful in disease. Several clinical trials are currently underway to test the therapeutic potential of drugs that enhance microglial capacity to phagocytose and multiply in numbers to restrain the pathology, while reducing microglial inflammation to prevent further damage to the brain. We may not even have yet uncovered all that microglia do in healthy brains and how they are involved in disease, and it’s important that the field continues to research fundamental microglia biology. Harnessing microglial functions alone may not be the cure for Alzheimer’s, a disease with many complex underlying mechanisms, but it has the potential to bring us closer to stopping the disease in its tracks before it’s too late. 

Gizem Terzioglu is a second year PhD candidate in the Neuroscience program at Harvard Medical School. She studies how microglial function and interactions with other cell types in the brain change in Alzheimer’s disease.

MJ Park is a third year PhD student in the Astronomy program at Harvard University. She studies the star formation and chemical enrichment of galaxies in the early Universe.

Cover image by geralt from pixabay.

For more information:

  • To learn about how microglia may be involved in Alzheimer’s disease and other neurodegenerative diseases such as MS, ALS and Parkinson’s disease, check out this review.
  •  Check out this website to learn more about how Alzheimer’s disease affects the brain.
  • Microglia do so many things in the brain! Check out this review to read more about microglia functions during development and adulthood.
  • Curious about how microglia may compact the structure of plaques to protect the brain? Check out this article to learn more.  
  • Microglia may not be the only immune cells affecting Alzheimer’s disease pathology in the brain! Check out this very recent paper showing that microglia recruit T cells, another type of immune cell normally found outside the brain, and how these two cell types may act together to advance neurodegeneration in the presence of tau pathology.

One thought on “Are microglia the hero or the villain in Alzheimer’s disease?

  1. Besides above mentioned functions like antagonizing beta-amyloid accumulation & formation and neutralizing tau protein – bearing neurofibrillar tangles, once the brain sugar metabolism is distrupted, microglia becomes a villain: after as a long-lived life of an uncelebrated hero – so to speak with regards to given (hopefully practical) analogy.

    Alzheimer’s and other dementia derivatives all seem to arise from chronic dysglycemic state of the brain. It is essentially Type 3 Diabetes that primarily affects brain metabolism & structural integrity. Once the glucose – usage efficiency is downregulated, a simultaneous rise of pro-inflammatory cytokines like TNF-A, Nf-Kappa B and Substance P while hindering the mRNA Expression of BDNF, NGF, IGF-1 and several other Neurotrophic Endogenous growth factors hence the full-scale mental deterioration.

    It was no surprise that several TNF-A Inhibitors and PGE1 Agonists produced dramatic acute improvements of Alzheimer’s sufferers due to above-stated theory. A number of compounds acting on those dual principle are currently on the competing pipelines.

    It is my sincere & firm hope that humankind will acquire potent agents that will effectively combat a variety of neurological diseases & ailments much sooner than currently anticipated.

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