Gut Health and the Progression of Alzheimer’s Disease

Illustrated by Eugenia Yoh

Alzheimer’s Disease has become one of the most wide-spread diseases affecting older populations, predicted to affect almost 14 million people in the next 30 years [1]. Due to the intricacies of the human brain, research in this field is continually cutting-edge, with new discoveries arising regularly. New research being conducted regarding  the relation of the gut microbiome and neurodegenerative diseases is promising, but poorly understood [2]. The term “microbiome” was coined at the turn of the 21st century, when a framework for understanding the wide-spread effects of gut microorganisms, including its influence on brain health, was being established. At one point, it was thought that brain functionality was localized to its structure, but advances in neurodegeneration research show that the balance of microbes in the gut has direct effects on the cause and progression of Alzheimer’s Disease [3] 

The gut brain axis is a denomination used to describe the bidirectional and “complex communication system”[4] that aims to “link emotional and cognitive centers of the brain with peripheral intestinal functions” [5]. The gut brain axis is used to describe the direct and indirect effect of gut health on brain health, two biological systems that were previously thought to exist and function independently of one another. In the last 20 years, there has been an increasing amount of experimental work that investigates the control of microbiota on the gut brain axis. Specifically, studies on mice have shown that germ-free mice, those that are born via cesarean section into a sterile environment, have lower anxiety levels and an increased stress response, compared to those born vaginally and into regular cage conditions [6]. These germ-free mice are thought to have more cognitive disorders as a result of their underdeveloped microbiomes. This is because the balance of microorganisms in the gut not only maintains gastro-intestinal health but also “interacts with CNS by regulating brain chemistry and influencing neuro-endocrine systems associated with stress response, anxiety and memory function”[7]

Recent studies have shown that the microbiota living in the guts of humans include bacteria, fungi, and viruses that, similarly to the microbiota of mice, have widespread effect on disorders of the central nervous system, specifically Alzheimer’s Disease. Alzheimer’s Disease can be characterized by the accumulation of specific proteins, brain inflammation, and death of neurons that lead to memory loss and overall dementia. There are two main ways that the microbiome influences Alzheimer’s disease development. The first is through increasing the build up of beta-amyloid plaques in the brain which disrupt neural communication and circuitry. The secretion of liposaccharides (LPS) and amyloids from bacteria residing in the gut are thought to be responsible for these plaques. Gram-negative bacteria are known to have LPS on their outer membrane, which is responsible for potentiating amyloid peptides [8]. In aging populations, the blood-brain barrier and the gastrointestinal tract tissue lining becomes more permeable, allowing for the amyloids to potentially travel from the gut into the blood-stream, through the blood brain barrier and into the brain. Thus, these bacteria indirectly lead to the build-up of beta-amyloid plaques in the brain that are involved in the development of Alzheimer’s Disease [9]. Studies have been conducted in mice models where mice have been injected intraperitoneally with doses of LPS to mimic an unbalanced microbiome. Jaeger et al. found that mice treated with LPS had significantly more beta amyloid plaques in their hippocampi and had seemingly consequential cognitive deficits as well [10], suggesting that the pathway triggered by LPS in the gut does indeed have neurodegenerative ramifications [11] 

The second way that the gut health affects the progression of Alzheimer’s disease is through the development of inflammatory conditions such as type 2 diabetes [12]. The blood-brain barrier, which is a highly selective semipermeable membrane, normally allows glucose to enter the brain from the bloodstream to clear away beta-amyloid build ups. However, vascular problems that are often side effects of low blood flow may hinder this process, and further, allows these plaques to collect in the brain [13]

Additionally, insulin resistance causes inflammatory responses in the body that are broadly characterized by an “increased expression of inflammatory agents that contribute to the onset of Alzheimer’s Disease[14]. Chronic inflammation in the brain is further exacerbated by the inactivation of neuron-nourishing, glial cell that are typically responsible for clearing waste and protein accumulations in the brain [15]. Insulin is known to promote the secretion of amyloid peptides from intracellular neuronal compartments. This signaling allows for a spike in amyloid peptide synthesis, additionally contributing to plaque build up [16]. Thus, diabetic patients who are medicated with insulin could be especially at risk for the over-production of amyloid proteins. 

Additionally, amyloid proteins are known to interfere with insulin receptor signalling in the brain, which leads to the abnormal processing of the protein tau. In many Alzheimer’s patients, the accumulation of the tau protein within neurons leads to internal tangles. Normally, in healthy neurons, tau binds to microtubules to stabilize the structure of the cell, but in Alzheimer’s patients, tau unhinges from these structural molecules as it gets hypophosphorylated and clumps to itself, ultimately disrupting electrical signaling, and neural communication [17]. Ultimately, the interference of insulin receptor signalling leads to an increase build up abnormal tau protein. 

Interestingly, Alzheimer’s patients often show a complex combination of inflammation and accumulation of abnormal tau and beta-amyloid proteins. There is strong evidence that shows that the gut microbiome directly impacts the development and progression of Alzheimer’s disease by contributing to both brain inflammation and protein build up through different pathways as shown here. These pathways are contained in the gut-brain axis which plays a large role in connecting the brain and the gut, two biological systems that used to be thought of as carrying out highly distinctive processes. As the complexities of these pathways within the gut-brain axis become better understood, future directions of Alzheimer’s research in treatment and prevention can be directed by what we now know about diversity of microbes in our guts and how their effects are vast and far-reaching.

Edited by: Irene Antony

Illustrated by: Eugenia Yoh

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