Theorizing on the Contribution of Gut Bacteria to Neurodegeneration

Researchers here propose a mechanism by which gut bacteria might accelerate the accumulation of misfolded proteins in the brain, known to be at the very least associated with various forms of neurodegenerative condition. Beyond mere corrleation, there is good evidence for the accumulation of aggregates of these broken proteins to be actively harmful, an important part of the disease process. The participation of gut bacteria doesn't mean we should focus on them, however; the right approach is to develop ways to safely and periodically remove these aggregates, classifying their presence as a form of damage to be repaired before it rises to harmful levels.

Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic Lateral Sclerosis (ALS) are all characterized by clumped, misfolded proteins and inflammation in the brain. Researchers have discovered that these processes may be triggered by proteins made by our gut bacteria (the microbiota). Their research has revealed that exposure to bacterial proteins called amyloid that have structural similarity to brain proteins leads to an increase in clumping of the protein alpha-synuclein in the brain. Aggregates, or clumps, of misfolded alpha-synuclein and related amyloid proteins are seen in the brains of patients with the neurodegenerative diseases AD, PD and ALS.

Alpha-synuclein is a protein normally produced by neurons in the brain. In both PD and AD, alpha-synuclein is aggregated in a clumped form called amyloid, causing damage to neurons. Researchers hypothesized that similarly clumped proteins produced by bacteria in the gut cause brain proteins to misfold via a mechanism called cross-seeding, leading to the deposition of aggregated brain proteins. They also proposed that amyloid proteins produced by the microbiota cause priming of immune cells in the gut, resulting in enhanced inflammation in the brain. The research involved the administration of bacterial strains of E. coli that produce the bacterial amyloid protein curli to rats. Control animals were given identical bacteria that lacked the ability to make the bacterial amyloid protein. The rats fed the curli-producing organisms showed increased levels of alpha-synuclein in the intestines and the brain and increased cerebral alpha-synuclein aggregation, compared with rats who were exposed to E. coli that did not produce the bacterial amyloid protein. The curli-exposed rats also showed enhanced cerebral inflammation.

Similar findings were noted in a related experiment in which nematodes (Caenorhabditis elegans) that were fed curli-producing E. coli also showed increased levels of alpha-synuclein aggregates, compared with nematodes not exposed to the bacterial amyloid. "These new studies in two different animals show that proteins made by bacteria harbored in the gut may be an initiating factor in the disease process of Alzheimer's disease, Parkinson's disease and ALS. This is important because most cases of these diseases are not caused by genes, and the gut is our most important environmental exposure. In addition, we have many potential therapeutic options to influence the bacterial populations in the nose, mouth and gut."

Link: https://www.eurekalert.org/pub_releases/2016-10/uol-sdr100516.php

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