Along with the increase in life expectancy in the populations of developed and developing countries resulting from better access and improved health care, the number of patients with dementia, including Alzheimer’s disease (AD), is growing. The disease was first diagnosed and described at the beginning of the 20th century. However, to this day, there is no effective causal therapy, and symptomatic treatment often improves patients’ quality of life only for a short time. The current pharmacological therapies are based mainly on the oldest hypotheses of the disease—cholinergic (drugs affecting the cholinergic system are available), the hypothesis of amyloid-β aggregation (an anti-amyloid drug was conditionally approved by the FDA in 2020), and one drug is an N-methyl-D-aspartate receptor (NMDAR) antagonist (memantine). Hypotheses about AD pathogenesis focus on the nervous system and the brain. As research progresses, it has become known that AD can be caused by diseases that have been experienced over the course of a lifetime, which could also affect other organs. In this review, we focus on the potential association of AD with the digestive system, primarily the gut microbiota. The role of diet quality in preventing and alleviating Alzheimer’s disease is also discussed. The problem of neuroinflammation, which may be the result of microbiota disorders, is also described. An important aspect of the work is the chapter on the treatment strategies for changing the microbiota, potentially protecting against the disease and alleviating its course in the initial stages.

/pdf/the-role-of-the-microbiota-gut-brain-axis-in-the-development-30b2hm0m.pdf

The Role of the Microbiota-Gut-Brain Axis in the Development of Alzheimer’s Disease

Amyloid-β (Aβ), the influence of which is considered the pathomechanism of Alzheimer’s disease, is also present in healthy people. The microbiome’s impact is also taken into account, where bacterial lipopolysaccharide (LPS) activates inflammatory processes and stimulates microglia via TLRs. Molecules of bacterial origin can co-create senile plaques with Aβ. This study evaluated the activity of physiological Aβ concentrations on neuronal and microglial cells after preincubation with LPS. Two cell lines were used in the study: PC12 cells differentiated with NGF and THP-1 cells differentiated with phorbol 12-myristate 13-acetate (PMA). Cells were incubated with LPS at concentrations of 1–100 μM for 24 h and then with Aβ25–35 at a concentration of 0.001 μM or 1.0 μM for another 24 h. The viability of the culture and free oxygen radicals and the number of DNA strand breaks in both cell lines were evaluated. Additionally, for PC12 cells, neural features were assessed. Stimulation of repair processes in the presence of Aβ was observed for both studied cell lines. There was a decrease in free radical level and DNA damage number compared to control cultures (cells treated with LPS and without Aβ). The neurotrophic activity of Aβ was observed—the effect on neurites’ growth even after the preincubation of PC12 cells with LPS. At the lowest concentration of LPS used, the increase in neurite length was about 50% greater than in the negative control. At low concentrations, Aβ has a protective effect on neuron-like PC12 cells pretreated with LPS.

/pdf/protective-activity-of-ab-on-cell-cultures-pc12-and-thp-1-2k06kt64zr.pdf

Protective Activity of Aβ on Cell Cultures (PC12 and THP-1 after Differentiation) Preincubated with Lipopolysaccharide (LPS)

Alzheimer's disease (AD), the most frequent cause of dementia, is a neurodegenerative disorder characterised by a progressive decline in cognitive function that is associated with the formation of amyloid beta plaques and neurofibrillary tangles. Gut microbiota comprises of a complex community of microorganisms residing in the gastrointestinal ecosystem. These microorganisms can participate in gut-brain axis activities, thereby affecting cognitive function and associated behaviours. Increasing evidence has indicated that gut dysbiosis can jeopardise host immune responses and promote inflammation, which may be an initiating factor for the onset and evolution of AD. Traditional Chinese medicine (TCM) is a promising resource which encompasses immense chemical diversity and multiple-target characteristics for the treatment of AD. Many TCMs regulate the gut microbiota during treatment of diseases, indicating that gut microbiota may be an important target for TCM efficacy. In this review, we summarised the role of the microbiota-gut-brain axis in the development of AD and the effects of TCM in treating AD by regulating the gut microbiota. We anticipate that this review will provide novel perspectives and strategies for future AD research and treatments. 

Traditional Chinese medicine for the treatment of Alzheimer's disease: A focus on the microbiota-gut-brain axis.

Background: Alzheimer’s disease is characterized by the deposition of senile plaques in the brain resulting in focal neurotoxicity that ultimately leads to neural network disruption. Intracellular calcium is a tightly regulated second messenger whose activation leads to numerous downstream events, including cell death. It has been suggested that dysregulation of calcium homeostasis plays a role in Alzheimer’s disease, however this has not been demonstrated directly. Methods: We combined in vivo multiphoton cell-resolved calcium imaging to quantitatively image resting and dynamic calcium signaling in both neurons and astrocytes in the brains of mouse models of AD. Results: We found that resting calcium was upregulated in neurons and throughout the astrocytic network in mice with cortical plaques. This increase in calcium levels in neurons, but not astrocytes, depended on the proximity to individual senile plaques. The neuronal calcium overload was not the result of presenilin mutations, and led to the loss of spino-dendritic compartmentalization, important for synaptic coordination. We also observed increased spontaneous calcium transients in astrocytes that were not dependent on neuronal activity. Astrocytes were functionally coupled across long distances in APP mice but not wildtype mice with evidence of in vivo intercellular calcium waves originating near plaques and spreading to astrocytes nearly 200 microns away. Conclusions: These data reveal disruptions in calcium homeostasis in both neurons and astrocytes in mouse models of AD with differing spatial associations. Together, the results demonstrate that the aberrant intracellular calcium levels in the brain provide insight into the pathophysiology of AD and that specific manipulation of calcium levels may lead to new drug targets.

Calcium dysregulation in Alzheimer's disease

The enteric nervous system (ENS) is considered by some authors as the second human brain, given its fundamental role in the regulation process of the central nervous system (CNS). Recent data from scientific literature have shown the existence of close bidirectional communication between the gut microbiota and the CNS, influencing physiological and biochemical changes related to cognition, emotion, behavior, anxiety, depressive symptoms, and stress. Furthermore, the existence of mediators in the connection between intestinal microorganisms and the CNS is evident, which includes neural networks, signaling, immune, and endocrine responses. However, the mechanisms underlying the effects of gut microbiota on brain processes still need to be determined. Therefore, understanding the relationship between the gut and neurodegenerative diseases (NDs) is essential for developing effective prophylactic alternatives and disease-modifying drugs that can prevent or slow the progression of such diseases. Herein, this short review aimed to present the most recent data from the scientific literature associated with the physiological, biochemical, and cellular aspects involved in the interrelationship between the gut-brain axis and NDs, discussing the role of the intestinal microbiota, and its relationship with CNS disorders.

The role of microbiota-gut-brain axis in neurodegenerative diseases: biochemical and therapeutic aspects

Functional interaction of the gastrointestinal tract (GI) and the central nervous system (CNS) is due to various relationships, which includes autonomic and enteral nervous systems as well as the immune and neuroendocrine systems. The microbiota of the macroorganism plays the central role in this interaction. Microbiota produces hundreds of biologically active substances that have a neurochemical effects through neuroendocrine, immune, and metabolic pathways. The microbiota also synthesizes and releases products (neurotoxins, neurotransmitters, lipopolysaccharides, amyloids, etc.) that can negatively affect the neurochemistry of the CNS, stimulating the development of amyloidosis, synucleinopathies, and tauopathies, thereby promoting the development and/or progression of neurodegenerative diseases. Under the influence of external and internal factors, human microbiota can be changed and the symbionts/pathogens ratio is also changed. The permeability of intestinal and blood-brain barrier varies. Metabolites produced by the altered microflora are able to enter the bloodstream and possibly into the CNS, thereby disrupting its functioning. Infections can play a significant role and even act as a cofactor in the induction of neurodegenerative diseases. Disturbance of the functions of the GI can precede long before the neurodegenerative processes. Early diagnosis, detection, monitoring, and treatment of negative gastrointestinal symptoms, including normalization of the microbiota, can lead to a significant improvement in the quality of life of patients with neurodegenerative diseases.

Role of Microbiota in Neurodegenerative Diseases

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Role of Microbiota in Neurodegenerative Diseases