The Role of Neuroinflammation in Alzheimer’s Disease

Alzheimer’s disease (AD) is a multifactorial disorder, and its most common symptoms include cognitive impairment, progressive memory decline, personality changes, and disorientation (1). AD is pathologically characterized by extracellular accumulation of amyloid-beta (Aβ) plaques and intracellular neurofibrillary hyperphosphorylated tau protein tangles (2). In neurodegenerative diseases such as AD, neuroinflammation initially acts as a defense mechanism for the brain by removing or inhibiting pathogens (3). While this response is initially beneficial, sustained inflammatory response becomes detrimental (3). Microglia and astrocytes are the principle cells responsible for this inflammatory response in the central nervous system, therefore gaining a greater understanding of these mechanisms can shed light on the processes that ultimately result in neurodegeneration (3). 

Microglia are the macrophages of the central nervous system (3,4). This means that they are involved in detecting changes to their environment, phagocytosis (ingestion of bacteria or other materials), and the destruction of bacteria and other harmful organisms (2,3). Depending on their activation status, microglia act in a proinflammatory or neuroprotective manner (3). When activated into their proinflammatory state by invading pathogens, microglia produce inflammatory mediators such as cytokines and reactive oxygen species which disturb neuronal function and result in cellular damage (4). While moderate activation provides protective effects, overactivation and sustained neuroinflammation could trigger and worsen the neurodegeneration seen in AD (3,4). Additionally, risk factors for AD such as obesity, insulin resistance, and type 2 diabetes are known to further induce the shift from neuroprotective to neurotoxic microglia (3). 

On the other hand, astrocyte cells regulate cerebral blood flow, maintain the blood-brain barrier and tight junctions, provide energy metabolites to neurons, and modulate synaptic activity within the brain (3). Similarly to microglia, astrocytes have both proinflammatory and immunoregulatory responses (3). Pathological astrogliosis, or an abnormal increase in numbers of astrocytes, is reported in AD patients (5). Additionally, astrocytes also assist with amyloid clearance, so dysregulation of these cells contributes to neuroinflammation and neurodegeneration (5).

In fact, both microglia and astrocyte cells interact with Aβ, and dysfunction of either cell type can result in accumulation of Aβ plaque (2). Excessive Aβ not only increases phosphorylation of tau protein, but also activates microglia and astrocytes to further release neuroinflammatory mediators that promote neurodegeneration (2,5). The neuroinflammatory environment then continues the inflammatory cycle by further activating the microglia and causing uncontrolled pro-inflammatory cytokine secretion, such that neurodegeneration is exacerbated (5). Neuroinflammation also causes microglia cells to be less effective at Aβ phagocytosis, thus contributing to the deposition of Aβ plaque seen in AD patients (5).

Current drugs used to treat AD only temporarily relieve symptoms and no medication has been found to stop or reverse the underlying process of the disease (6). Drugs targeting Aβ or tau have been at the forefront of many clinical trials. However, with recent advances in the understanding of chronic inflammation induced by microglia and astrocytes in AD, these highlight other potential targets for AD treatment (6). More recent studies have found that nonsteroidal anti-inflammatory drugs (NSAID) reduce microglial activation and amyloid burden in animal models, but failed to show significant change in clinical settings (5). These studies cite the idea that the activation states of microglia and neuroinflammatory environments are constantly changing in AD progression, so timing of intervention will play a critical role in anti-inflammatory therapeutic approaches (5). 

Esurgi is currently developing Eye AD which utilizes the specific patterns of saccadic eye movement to monitor and diagnose for the disease (7). In the future, drug therapy can be used in conjunction with products such as Esurgi’s Eye AD to better address the multifactorial nature of AD and work towards earlier detection and treatment. 

Sources:

1. Rusek, M., Pluta, R., Ułamek-Kozioł, M., & Czuczwar, S. J. (2019). Ketogenic Diet in Alzheimer’s Disease. International Journal of Molecular Sciences, 20(16). https://doi.org/10.3390/ijms20163892
2. Wilkins HM, Swerdlow RH. Relationships Between Mitochondria and Neuroinflammation: Implications for Alzheimer’s Disease. Curr Top Med Chem. 2016;16(8):849-857 doi: 10.2174/1570159X15666170720095240
3. Kwon HS, Koh S-H. Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Transl Neurodegener. 2020;9. doi:10.1186/s40035-020-00221-2
4. Fakhoury M. Microglia and Astrocytes in Alzheimer’s Disease: Implications for Therapy. Curr Neuropharmacol. 2018;16(5):508-518. doi:10.2174/1570159X15666170720095240
5. Minter MR, Taylor JM, Crack PJ. The contribution of neuroinflammation to amyloid toxicity in Alzheimer’s disease. Journal of Neurochemistry. 2016;136(3):457-474. doi:https://doi.org/10.1111/jnc.13411
6. Dong Y, Li X, Cheng J, Hou L. Drug Development for Alzheimer’s Disease: Microglia Induced Neuroinflammation as a Target? Int J Mol Sci. 2019;20(3). doi:10.3390/ijms20030558
7. Panchal H, De A, Agbakwuruonyike C, Jiang Y, Kanjoo P. Literature Review on the Correlation Between Abnormalities in Eye Movement and the Presence of Alzheimer Disease. Published online 2020:7.