By Michelle Lam
Alzheimer’s disease (AD) is the leading cause of dementia, affecting over 50 million people worldwide.1 With improvements in global health, dementia cases are projected to triple by 2050.2 Despite advancements in understanding disease progression, there are still no disease-modifying therapies available. Therefore, it is crucial that new biomarkers are identified to overcome this.1 Currently, the accepted model for AD pathogenesis is the amyloid cascade hypothesis, which states that neurodegeneration is the result of the accumulation of extracellular amyloid beta (Aβ) plaques within various regions of the brain. This triggers a cascade of events, such as the formation of intracellular neurofibrillary tangles (NFTs), and neuroinflammation through increased microglia and astrocyte activation, which eventually leads to neuronal death.3
More recently, the gut-brain axis and microbiota have been identified as potential modulators of AD progression. The gut-brain axis is the bidirectional communication between the CNS and the gut microbiota through microbiota-associated metabolites (MAMs); the enteric and autonomic nervous systems; the immune system; and the hypothalamic-pituitary-adrenal (HPA) axis.4-5 The gut-brain axis is involved in processes such as regulating blood-brain barrier (BBB) integrity, food intake and brain behaviour, and is also implicated in disorders such as irritable bowel syndrome and obesity.4 Gut dysbiosis refers to alterations in the gut microbiota, often caused by ageing, antibiotics, and high-fat diet (HFD).6 Gut dysbiosis has been observed in faecal samples of AD patients, with reports showing an increase in Bacteroides and decreased Bifidobacterium compared to controls.7Moreover, Saiyasit et al. demonstrated that HFD-induced gut dysbiosis in rodents resulted in systemic inflammation, and thus, microgliosis (microglial activation) and hippocampal dysplasia, giving further evidence of the role of the gut microbiota in AD.8
The exact mechanism by which gut dysbiosis may influence AD is unknown, although evidence suggests that it could be through modulation of BBB permeability. The BBB lines the blood vessels of the CNS and has a cardinal role in maintaining homeostasis in the brain. It is a barrier that must be tightly regulated, as it must allow sufficient blood flow to meet the high metabolic demand of the brain and allow the passage of important ions and nutrients. On the contrary, it must also protect it from dangerous threats such as blood-borne pathogens and anaphylatoxins. The BBB is enriched with tight junctions at the endothelium, which are protein complexes of predominately claudins and occludins which bind to tight junctions on adjacent cells. This creates a seal that prevents the flow of ions and solutes between endothelial cells, which is known as the paracellular pathway.9 Germ-free mice, which lack a microbiota, and antibiotic-treated mice, have been reported to have decreased levels of claudin-5 and occluding.10-11Thus, an altered gut microbiota could increase BBB permeability through modulation of tight junctions. This allows toxic molecules to bypass the BBB, such as CCL11, a risk factor of late onset AD. CCL11 can modulate glial cells and promote the formation of amyloid-beta plaques.12 Furthermore, lipopolysaccharides (LPS), a major component of Gram-negative bacterial cell membranes, can be secreted by the intestinal microbiota and bind to toll-like receptor (TLR) 4.13 Activated TLR4 downregulates tight junction proteins, which allows neurotoxins, including LPS itself, to cross the BBB.14 LPS can bind then bind to TLR4 on microglial cells and promote the production of inflammatory cytokines through NF-κB signalling, which may accelerate amyloidosis and AD pathogenesis.13,15
In addition, another way in which the gut microbiota may contribute to AD pathogenesis is through the production of bacterial amyloids. Bacteria produce amyloids to facilitate binding to other bacterial cells in order to create a biofilm, and also to evade the immune system. Bacterial amyloids have a different primary structure to the CNS-produced Aβ, however, share similarities in their tertiary structures. Because of this, it is possible that the presence of gut bacterial amyloids primes the immune system for amyloid attack, which results in a greater immune response to endogenously produced amyloids.16 Curli is an example of a bacterial amyloid, produced by Escherichia coli. A study by Chen et al. found that when rats were exposed to Curli-producing E. coli, increased amounts of Aβ in the gut and brain, along with elevated astrogliosis and microgliosis, were observed compared to control rats which were exposed to non-Curli-producing bacteria. The study also determined that there was expression of the immune markers TLR2, interleukin-6 and TNF were upregulated in the E. coli exposed rats, providing more evidence that these rats had enhanced neuroinflammation.17 Bacterial amyloids may promote amyloidosis through molecular mimicry, in which the bacterial amyloids act as prion proteins that cause another amyloid protein to misfold into the pathogenic β-sheet structure.16,18
The novel role of the gut microbiota in AD has revealed the potential for new therapeutic interventions, one being the administration of probiotics. A study found that Enterococcus faecium and Lactobacillus rhamnosus supplementation lowered TNF-alpha production, reduced reactive oxygen species production and upregulated antioxidant enzyme activity in the brain, suggesting that these probiotics could alleviate neuroinflammation in the brain.19 Perhaps the best characterised probiotics are those belonging to the Lactobacillus and Bifidobacteria genera. Several studies have provided evidence of the potential of these probiotics to treat AD. In a clinical study, Lactobacilli and Bifidobacteria probiotics were administered to AD patients and the results found that the Mini-Mental State Examination scores, a test that assesses the severity of dementia, significantly improved in the patients.20 One study suggested that these probiotics could work by acetylcholinesterase (AchE) inhibition. LPS-treated mice who were supplemented with Lactobacilli probiotics had improved memory, compared to LPS-treated controls who were not administered with probiotics, and this was accompanied with AchE inhibition.21 The study also hypothesised that the observed decrease of neuroinflammation in the Lactobacillus supplemented mice could be partly due to AchE inhibition, formed on the basis that previous studies have reported that administration of AchE inhibitors has reduced neuroinflammation and neurodegeneration in the hippocampus and cortex of rodents.21-22
Currently, AD is diagnosed on cognitive dysfunctions, however it can be up to 20 years after onset before these are observed. Thus, there is a pressing need for the design of disease-modifying therapies for AD that can delay the irreversible neurodegeneration.23 It is clear that the amyloid cascade hypothesis cannot fully explain the pathogenesis of AD due to the lack of success of anti-Aβ therapies.24 One of the main problems in discovering a successful disease-modifying therapy is the lack of biomarkers for early detection. Therefore, the growing body of knowledge regarding the role of the gut microbiota in the disease will aid in understanding disease progression and designing suitable biomarkers for AD.23 New therapeutics will also ameliorate the socioeconomic burden that AD imposes. For instance, Alzheimer’s association reported a total cost of $236 billion associated with AD, which will only increase, with the expected exponential increase in cases, if a cure is not found.25 Since the role of the gut microbiota in AD is a relatively new concept, more research can be conducted in investigating the ways in which the gut microbiota can be manipulated to treat AD.
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