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Removing Dysfunctional Microglia Prevents Amyloid-β Plaques

Targeting these immune cells may help treat Alzheimer's disease.

Glia Alzheimer'sGlia Alzheimer's

The macrophages resident in the brain and spinal cord appear to be a key element in the progression of Alzheimer’s disease, according to the results of a new mouse study.

Microglial mayhem

As we age, our immune cells become increasingly dysfunctional; once-helpful cells can behave in harmful ways, promoting persistent inflammation, impairing tissue regeneration, and possibly also facilitating the progression of age-related diseases. This process of immune decline is known as immunosenescence and is at least partly linked to stem cell exhaustion, one of the nine reasons we age.

The microglia are one such population of immune cells located in the brain, and, as the new study shows, they are important in the development and progression of Alzheimer’s disease [1].

Microglial cells are a specialized population of tissue-resident macrophages that are found throughout the brain and spinal cord, which, together, are known as the central nervous system (CNS). Microglia account for 10–15% of all cells found within the brain and spinal cord region, and they act as the first line of immune defense in the CNS. They remove damaged neurons and combat infections, allowing the health of the CNS to be maintained.

It seems likely that not only do some microglia in the brain become senescent during aging, but some also remain alive but dysfunctional, altering their behavioral program (polarization).

The polarization of macrophages

There are two main polarizations in macrophages: M1 and M2. In simple terms, M1 macrophages aggressively intercept pathogens and are pro-inflammatory, as they deploy various weaponized secretions against invading bacteria and viruses. In contrast, M2 macrophages are focused on reducing inflammation to facilitate tissue repair and healing.

Under normal conditions, both polarizations are needed to maintain defenses and keep tissue healthy; however, during aging, the ratio of M1 to M2 microglia (and other macrophages elsewhere in the body) becomes unbalanced and swings towards the inflammatory M1 type rather than the healing M2.

One reason that macrophage behavior is thought to shift like this is due to the loss of autophagy [2] as well as the increasing chronic background of inflammation known as “inflammaging”, which encourages macrophages to swing towards the M1 type. This means that as we age and our chronic inflammation increases, more and more macrophages, including microglia, shift towards this M1 profile.

The researchers in this new study have demonstrated that removing dysfunctional microglia is able to prevent the formation of the amyloid-ß plaques that typically accompany Alzheimer’s disease [3].


Many risk genes for the development of Alzheimer’s disease (AD) are exclusively or highly expressed in myeloid cells. Microglia are dependent on colony-stimulating factor 1 receptor (CSF1R) signaling for their survival. We designed and synthesized a highly selective brain-penetrant CSF1R inhibitor (PLX5622) allowing for extended and specific microglial elimination, preceding and during pathology development. We find that in the 5xFAD mouse model of AD, plaques fail to form in the parenchymal space following microglial depletion, except in areas containing surviving microglia. Instead, Aß deposits in cortical blood vessels reminiscent of cerebral amyloid angiopathy. Altered gene expression in the 5xFAD hippocampus is also reversed by the absence of microglia. Transcriptional analyses of the residual plaque-forming microglia show they exhibit a disease-associated microglia profile. Collectively, we describe the structure, formulation, and efficacy of PLX5622, which allows for sustained microglial depletion and identify roles of microglia in initiating plaque pathogenesis.


The decline and dysfunction of the immune system is clearly implicated in the development of Alzheimer’s, disease as this study shows. The results of this study also offer potential inroads for the development of therapies that may be able to deal with problem microglia.

An overall approach that should also improve the situation is the effective management of chronic inflammation, and therapies that remove the sources of that inflammation, such as senescent cells, may also help restore healthy immune function in the CNS. Targeting populations of senescent microglia in particular may help achieve this.

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[1] Spangenberg, E., Severson, P. L., Hohsfield, L. A., Crapser, J., Zhang, J., Burton, E. A., … & Habets, G. (2019). Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model. Nature communications, 10(1), 1-21.

[2] Jin, M., Wang, F., Liu, W., Qi, D., Gu, C., Mao, C. J., … & Liu, C. F. (2018). A critical Role of autophagy in regulating microglia polarization in neurodegeneration. Frontiers in aging neuroscience, 10, 378.

[3] Spangenberg, E., Severson, P. L., Hohsfield, L. A., Crapser, J., Zhang, J., Burton, E. A., … & Green, K. N. (2019). Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model. Nature communications10(1), 1-21.

About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 600 articles on the topic, interviewed over 100 of the leading researchers in the field, hosted livestream events focused on aging, as well as attending various medical industry conferences. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, Swiss Monthly, Keep me Prime, and New Economy Magazine. Steve is one of three recipients of the 2020 H+ Innovator Award and shares this honour with Mirko Ranieri – Google AR and Dinorah Delfin – Immortalists Magazine. The H+ Innovator Award looks into our community and acknowledges ideas and projects that encourage social change, achieve scientific accomplishments, technological advances, philosophical and intellectual visions, author unique narratives, build fascinating artistic ventures, and develop products that bridge gaps and help us to achieve transhumanist goals. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project.
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