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What is Beta-Amyloid?
What is Beta-Amyloid?
With regard to Alzheimer's, beta-amyloid is a protein that forms from the breakdown of the amyloid precursor protein (APP). Very little is known about the function of amyloid proteins in a healthy brain. It is speculated that they help with transportation of cells and communication between them, but not enough research has been done to say for sure. But, in an AD model brain, βA forms and begins to abnormally accumulate into toxic plaques in between neurons, stunting cell function and often causing cell death. We will look at a specific process the happens naturally in the body called phagocytosis that attempts to combat these accumulations.
Microglia & TAM Receptors
Microglia & TAM Receptors
Microglia play an integral part in the breakdown of beta-amyloid plaques. Their main role concerning Alzheimer's is to conduct phagocytosis. TAM receptors (Tyro3, Axl, and MerTK) are a family of kinases in which their main responsibility is to help in the process of conducting phagocytosis in the presence of unwanted bacteria or other material, such as our target beta-amyloid plaques. With regard to Alzheimer's, two of the three receptors (Axl and Mer) are expressed on the microglia and are very important to the function of the microglia in the recognition, engulfment, digestion and response to the plaques (Tyro3 are expressed on neurons). The study below looks at the concentrations of these proteins expressed, in proper physiological conditions, in both wildtype mice and mice that carry a mutation of the APP gene, resembling the human model of an AD patient.
Process of Phagocytosis
Process of Phagocytosis
The leftmost Figure B panels show Axl proteins (green) stained on the microglia (red). The rightmost panels of Figure B show the beta-amyloid plaques (white) stained on the former microglia (nuclei stained in blue). In Figure C, the leftmost panels show Mer proteins (green) overlying the microglia (red) while the rightmost panels show the beta-amyloid plaques (white) overlying the microglia (nuclei stained in blue). These two figures confirm the expression of both Axl and Mer on microglia (Huang et al.).
Experimental Approach
Experimental Approach
After confirming the up-regulation of TAM receptors within microglia (pictured above), the researchers used transgenic mice models to compare "WT" AD models (APP/PS1), TAM deficient models (Axl−/−Mertk−/−), and AD/TAM deficient models (APP/PS1Axl−/−Mertk−/−) and the concentrations of plaques phagocytized by microglia in each condition. An intraperitoneal injection of MX04 - a fluorescent marker - was used to quantify the concentrations and imaged through immunohistochemistry. In the figure to the left, the researchers specifically compared the concentration of βA plaques in the "WT" AD models (APP/PS1 (A/PS)) and AD/TAM deficient models (APP/PS1Axl−/−Mertk−/− (A/PS A/M−/−)). They found that the microglia in the AD/TAM deficient model engulfed about 10-fold less volume of MX04-labelled plaque material compared to the WT AD model.
After confirming the up-regulation of TAM receptors within microglia (pictured above), the researchers used transgenic mice models to compare "WT" AD models (APP/PS1), TAM deficient models (Axl−/−Mertk−/−), and AD/TAM deficient models (APP/PS1Axl−/−Mertk−/−) and the concentrations of plaques phagocytized by microglia in each condition. An intraperitoneal injection of MX04 - a fluorescent marker - was used to quantify the concentrations and imaged through immunohistochemistry. In the figure to the left, the researchers specifically compared the concentration of βA plaques in the "WT" AD models (APP/PS1 (A/PS)) and AD/TAM deficient models (APP/PS1Axl−/−Mertk−/− (A/PS A/M−/−)). They found that the microglia in the AD/TAM deficient model engulfed about 10-fold less volume of MX04-labelled plaque material compared to the WT AD model.
Summary
Summary
TAM receptors expressed on microglia play an important role to the process of phagocytosis. And, relative to the pathology of AD, phagocytosis is a very important process in attempting to reduce the number of beta-amyloid plaques that form in the brain. After confirming that TAM receptors are in fact expressed on microglia, the study above not only indicates that models susceptible to developing Alzheimer's by containing a mutation of the APP gene are susceptible to declined microglia function, but that the AD model with the ablated TAM receptor function was even more susceptible to declined microglia function, almost completely abolished in fact. By using the AD mouse model as their baseline, or "WT," the researchers were truly able to support this claim.
References
References
Huang, Y, et al. Microglia use TAM receptors to detect and engulf amyloid beta plaques. Nat Immunol. 2021 May;22(5):586-594. doi: 10.1038/s41590-021-00913-5. Epub 2021 Apr 15. PMID: 33859405; PMCID: PMC8102389.
Huang, Y, et al. Microglia use TAM receptors to detect and engulf amyloid beta plaques. Nat Immunol. 2021 May;22(5):586-594. doi: 10.1038/s41590-021-00913-5. Epub 2021 Apr 15. PMID: 33859405; PMCID: PMC8102389.
Janda, E., et al. Microglial Phagocytosis and Its Regulation: A Therapeutic Target in Parkinson’s Disease? Front. Mol. Neurosci., 27 April 2018, Sec. Brain Disease Mechanisms, Vol. 11. https://doi.org/10.3389/fnmol.2018.00144.
U.S. Department of Health and Human Services. (2017, May 16). What Happens to the Brain in Alzheimer's Disease? National Institute on Aging. Retrieved March 22, 2023, from https://www.nia.nih.gov/health/what-happens-brain-alzheimers-disease#:~:text=Amyloid%20plaques,thought%20to%20be%20especially%20toxic
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