Friedland has studied Alzheimer’s disease, dementia and related conditions for more than 30 years. His previous work has uncovered the such as Amyotrophic Lateral Sclerosis (ALS, also known as Lou Gehrig’s disease), Alzheimer’s disease and Parkinson’s disease. Previously, Friedland worked with researchers at the National Cerebral and Cardiovascular Center in Osaka to reveal the important influence of oral bacteria on the development of hemorrhagic stroke.

In Kyoto, Friedland will further investigate the influence of the microbiota on neurodegenerative disease models in fruit flies. He plans tests to determine the influence of functional bacterial amyloid proteins on the aggregation of brain proteins, a key element of neurodegenerative diseases. Friedland will collaborate in this research with Toshiki Mizuno, PhD, of the KPUM Division of Neurology and Gerontology, one of several Japanese researchers with whom Friedland has worked for several decades.

He also will conduct research with collaborators at the Kyoto Institute of Technology.

“I am excited to have the opportunity to collaborate further with my Japanese colleagues and to conduct this research in Kyoto,” Friedland said.

JSPS awards fellowships to select international researchers to conduct collaborative work with researchers in Japan. Long-term fellowships for 2020 have been awarded in agriculture, engineering, chemistry, math, humanities and medicine. Friedland received one of four fellowships in the field of medicine.

After his year in Kyoto, Friedland will continue his research and clinical work at UofL, where his collaborators in the lab of Levi Beverly, PhD, currently are finishing data analysis on a study of the influence of bacterial amyloid on ALS in mice.

University of Louisville neurology professor and professor at the University of Michigan, have proposed a new term to describe an interaction between gut microbiota and the brain in an article released today in .

Friedland and Chapman propose the term “mapranosis” for the process by which amyloid proteins produced by microbes (bacteria, fungi and others) alter the structure of proteins (proteopathy) and enhance inflammation in the nervous system, thereby initiating or augmenting brain disease. The term is derived from Microbiota Associated Protepathy And Neuroinflammation + osis (a process).

Friedland hopes that giving the process a name will facilitate awareness and research leading to therapeutic opportunities.

“It is critical to define the ways in which gut bacteria and other organisms interact with the host to create disease, as there are many ways in which the microbiota may be altered to influence health,” Friedland said.

Research into the multitude of microbes that inhabit the human body has expanded considerably in recent years. Genomic analysis has begun to reveal the full diversity of bacteria, viruses, fungi, archaea and parasites living in and on the body, the majority of them in the gut. Even more recently, researchers have begun to explore how the proteins and other metabolites produced by microbes in the gut influence functions in other parts of the body, including the brain. However, we do not yet fully understand how these systems work. The relationship between the microbiota and the brain has been called the “gut-brain axis.”

It is understood that the clumping of misfolded amyloid proteins, structures produced by neurons in the brain, are associated with neurodegeneration and conditions such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis (ALS).

“It is well known that patterns of amyloid misfolding of neuronal proteins are involved in age-related brain diseases. Recent studies suggest that similar protein structures produced by gut bacteria, referred to as bacterial amyloid, may be involved in the initiation of neurodegenerative processes in the brain,” Friedland said. “Bacterial amyloids are produced by a wide range of microbes that inhabit the GI tract, including the mouth.”

In research published in 2016 in , Friedland and colleagues showed that when E. coli microbes in the gut of rats and worms (nematodes) produced misfolded amyloids, the amyloids produced in the animals’ brains and intestines also misfolded, a process called cross-seeding.

“Our work suggests that our commensal microbial partners make functional extracellular amyloid proteins, which interact with host proteins through cross-seeding of amyloid misfolding and trigger neuroinflammation in the brain,” Friedland said.

In today’s article, Friedland and Chapman also address other factors related to the microbiota and its products and how they influence neurodegenerative disorders.

1. The microbiota modulates (enhances) immune processes throughout the body, including the central nervous system.
2. The microbiota may induce oxidative toxicity (free radicals) and related inflammation that contributes to neurodegeneration.
3. Metabolites produced by the microbiota may be either beneficial (health sustaining) or damaging (pathogenic).
4. Host genetics influence microbiota populations, illustrating that the gut-brain axis is bidirectional.

Friedland believes further research in this area may lead to therapies for these neurodegenerative diseases, which are increasing in frequency and for which there are few effective treatments.

Robert Friedland, MD, professor in the Department of Neurology at the University of Louisville, has conducted research showing that the microorganisms in the intestines can affect the brain, and may be responsible for causing Alzheimer’s, Parkinson’s and other neurodegenerative diseases. He will discuss this research and other valuable insights on microbiota at the next event, Feb. 15. 

“These partner microbes have more than 100 times more genes than our own DNA. Since they are dependent upon our diet for their nutrition and sustenance, we can substantially alter the microbiota through alteration of food intake, performing a type of ‘gene therapy,’” Friedland said. “We will discuss the role of the microbiota in health and disease and review what people can do to lower their risk of cancer, stroke, and Alzheimer’s and Parkinson’s diseases.”

Friedland is a clinical and research neurologist and has researched neurodegenerative diseases and other brain disorders associated with aging for more than 30 years. He is collaborating on research projects with investigators in Ireland, the United Kingdom and Japan.

The Beer with a Scientist event begins at 8 p.m. on Wednesday, Feb. 15, at Against the Grain Brewery, 401 E. Main St. in Louisville. A 30-minute presentation will be followed by an informal Q&A session. Admission is free. Purchase of beer, other beverages or menu items is not required but is encouraged.

The next Beer with a Scientist is scheduled for March 15.

Robert P. Friedland, MD, the Mason C. and Mary D. Rudd Endowed Chair and professor of Neurology at the University of Louisville School of Medicine, and a team of 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 (AS) 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. Friedland has 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. He 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, which was supported by , 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 AS in the intestines and the brain and increased cerebral AS 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 AS aggregates, compared with nematodes not exposed to the bacterial amyloid. A research group led by neuroscientist Shu G. Chen, PhD, of Case Western Reserve University, performed this collaborative study.

This new understanding of the potential role of gut bacteria in neurodegeneration could bring researchers closer to uncovering the factors responsible for initiating these diseases and ultimately developing preventive and therapeutic measures.

“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,” Friedland said. “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.”

Friedland is the corresponding author of the article, , published online Oct. 6 in Scientific Reports, a journal of the Nature Publishing Group. UofL researchers involved in the publication in addition to Friedland include Vilius Stribinskis, PhD, Madhavi J. Rane, PhD, Donald Demuth, PhD, Evelyne Gozal, PhD, Andrew M. Roberts, PhD, Rekha Jagadapillai, Ruolan Liu, MD, PhD, and Richard Kerber, PhD. 

This work supports recent studies indicating that the microbiota may have a role in disease processes in age-related brain degenerations. It is part of Friedland’s ongoing research on the relationship between the microbiota and age-related brain disorders, which involves collaborations with researchers in Ireland and Japan.

“We are pursuing studies in humans and animals to further evaluate the mechanisms of the effects we have observed and are exploring the potential for the development of preventive and therapeutic strategies,” Friedland said.