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With the increasing longevity of the global population, Alzheimer’s disease (AD), characterized by a progressive decline in cognitive function and memory, and marked by pathological features such as amyloid-beta (Aβ) plaques, neurofibrillary tangles, and neuroinflammation have become one of the most significant health challenges.

“… over 400 clinical trials targeting brain-derived Aβ have not proven to be very effective.”

The traditional “Amyloid Cascade” hypothesis suggests that the accumulation of the protein amyloid beta (Aβ) in the brain triggers a series of events leading to AD. However, over 400 clinical trials targeting brain-derived Aβ have not proven to be very effective. This has led researchers to explore other potential contributors to AD pathology, which are discussed in a review article recently published by Zoe AP Williams and colleagues in the journal Microbial Biotechnology. One of the intriguing aspects discussed in this article is the role of Aβ as an antimicrobial peptide.

“…[there are] various microbial influences, such as the herpes simplex virus type 1 (HSV1), which has been linked to AD through its ability to seed Aβ and its preference for brain regions affected by AD.”

In contrast to the earlier view that Aβ plays a causative role in AD, it has been suggested that it is part of the brain’s response to defend itself against invading pathogens, and increased levels of microbes have been found in the brains of AD patients. The article delves into various microbial influences, such as the herpes simplex virus type 1 (HSV1), which has been linked to AD through its ability to seed Aβ and its preference for brain regions affected by AD. Moreover, bacterial infections, particularly with Porphyromonas gingivalis, a Gram-negative anaerobic bacterium, which is the major etiological agent contributing to chronic periodontitis have been implicated in AD through the production of toxic proteases that correlate with tau pathology.

“The microbiota-gut-brain system is emerging as a key area of investigation in AD.”

The article by Dr. Williams and colleagues also highlights the gut-brain axis and the role of the gut microbiome in AD. Changes in gastrointestinal physiology during aging can lead to alterations in the gut microbiota, which may influence the brain. The microbiota-gut-brain system is emerging as a key area of investigation in AD, with studies showing that alterations in gut microbiota composition are associated with AD. This includes a decrease in microbial diversity and an increase in pro-inflammatory genera, which correlates with increased expression of pro-inflammatory cytokines in the blood. As discussed repeatedly in the blog and in my book, The Mind Gut Immune Connection, studies have shown that the gut microbiome can interact with the host and regulate its immune system, potentially contributing to inflammatory changes in the gut, in the systemic circulation and in the brain. Recent research suggests that the gut microbiome, influencing the brain might play a significant role in AD pathology.

“The study aimed to explore a causal relationship between gut microbiota alterations and AD.”

A team of Irish and Italian investigators under the leadership of Yonne Nolan from the Department of Anatomy and Neuroscience, University College Cork, Ireland recently published results from a study entitled “Microbiota from Alzheimer’s patients induce deficits in cognition and hippocampal neurogenesis” in the journal Brain. The study aimed to explore a causal relationship between gut microbiota alterations and AD. Alzheimer’s disease, characterized by progressive cognitive decline and neuropsychiatric symptoms, is traditionally linked to characteristic neuropathological changes including Aβ plaques, tau tangles, and neuroinflammation.

To test the hypothesis about causality between the gut microbiome and these brain changes, researchers transplanted fecal microbiota from AD patients and age-matched healthy controls into young adult rats whose microbiome had been depleted by a course of broad-spectrum antibiotics. Such human to rodent fecal transplant studies have become the state-of-the-art experimental approach to demonstrate that gut microbial changes observed in well characterized human patients play a causal role in the pathophysiology of AD and other brain disorders, including Parkinson’s disease and depression.

“…rats receiving such a transplant of microbiota from AD patients exhibited significant impairments in behaviors dependent on hippocampal neurogenesis.”

They also observed that rats receiving such a transplant of microbiota from AD patients exhibited significant impairments in behaviors dependent on hippocampal neurogenesis. Neurogenesis refers to the unique ability of cells which are precursors of neurons in this brain region to generate new cells and replace neuronal losses. The observed impairments were correlated with the cognitive scores of the donor patients, indicating that gut microbiota alterations could directly impact cognitive functions. Additionally, changes in gut microbial metabolites in the rats’ large intestine and hippocampus were noted, pointing to a systemic effect of the transplanted microbiota.

In addition to the microbial transplants, the study also explored the impact of molecules in the systemic circulation on neurogenesis using human serum samples in vitro. Serum from AD patients decreased neurogenesis in human hippocampal progenitor cells, correlating with cognitive scores and specific microbial genera.

Moreover, the researchers found that the gut microbiota from AD patients induced significant alterations in the intestinal characteristics of the recipient rats, including increased fecal water content, reduced colon length, hyperplasia of crypts, and loss of mucus producing cells. These changes suggest that in addition to their effects on the brain, the gut microbiota from AD patients can disrupt gut health and function in the recipient organism.

“The involvement of microbes in AD opens new avenues for treatment development”

In conclusion, the article posits that microbes may play a significant role in AD pathology. The findings are not in opposition to existing hypotheses about AD pathophysiology, but rather as a unifying factor that could explain the presence of Aβ and inflammation in AD. The involvement of microbes in AD opens new avenues for treatment development, emphasizing the need for a better understanding of the complex interactions between microbes, the immune system, and neurodegeneration. This understanding could lead to novel therapeutic and prophylactic strategies for managing AD.