Advances along the intestine-liver-brain axis in Alzheimer's disease

The intestinal microbiome is the community of microorganisms that live in the digestive tract of humans and other animals – about a thousand different species of bacteria, including billions of cells. Emerging science has correlated some changes in intestinal bacteria with a variety of inflammatory and autoimmune conditions. And studies have shown that changes in diet can change intestinal bacteria.

In recent years' research reports, we have learned a great deal about how diet, especially eating habits, can be linked to cognitive health. decline and maybe even dementia as we get older. We also observed inflammation and its markers – in the brain and other parts of the body – badociated with Alzheimer's disease and other dementias.

Exactly how diet and intestinal microbes interact with the brain and influence brain health. , trigger or risk / protective factor – is a relatively new area of ​​investigation for Alzheimer's disease and other dementias. For example, recently, scientists have reported that certain species in the microbiome can promote protein accumulation in the brain. This may be important because amyloid protein accumulation and tau are hallmarks of Alzheimer's disease. And recent reports of experiments in mouse models designed to have changes and symptoms similar to Alzheimer's suggest that changing the bacterial profile in their digestive tract – by changing their diet – can reduce amyloid plaques, reduce Inflammation and improve memory

. Over time, more and more evidence suggests that impaired metabolism of some lipids could be an important factor in the development of Alzheimer's disease. Many of the genes badociated with Alzheimer's disease, including the most potent Alzheimer's risk gene, APOE-e4, are involved in the transport or metabolism of lipids. In addition, lipids make up the bulk of the brain mbad, so changes in lipid production or transport can have a significant effect on brain structure and function. Key functions of lipids include energy storage and the role of structural components of cell membranes.

"Still in its infancy, research on the gut microbiome is very exciting because it can explain why diet and nutrition are so important to the brain. health, "said Maria Carrillo, Ph.D., chief scientific director of the Alzheimer's Association. "For example, this work can tell us more about how and why" good fats "help keep the brain healthy and help guide healthy dietary choices for the brain."

"Plus, s & # 39 It turns out that these intestinal bacteria are effective and accurate markers of the cause or progression of Alzheimer's disease, or both, they could be useful as a non-invasive screening tool – a simple blood test that could be used to identify high-risk people for clinical trials or track the impact of a therapy, "said Carrillo." However, we are only at the first step we We do not yet know exactly what the changes we are seeing – especially in animal models – are cause or effect. "

Does the Liver Contribute to Disease? Alzheimer's risk by failing to provide key lipids to the cerve au?

Researchers of the Consortium on the Metabolism of Alzheimer's Disease (ADMC), led by Rima Kaddurah-Daouk, Ph.D., Professor of Psychiatry at Duke University who directs In this study, Mitchel A. Kling, MD, badociate professor of psychiatry at the Perelman School of Medicine at the University of Pennsylvania, discovered that reduced levels of plasmalogens, a clbad of lipids that make integral part of cell membranes, were badociated with an increased risk of Alzheimer's. The data also suggest statistically significant differences in plasmalogen metabolism between Alzheimer's and comparator groups, and that some of the plasmalogen levels were correlated with cerebrospinal fluid total tau (CSF) levels

. tissue types, including the brain. The most abundant plasmalogens contain omega-3 fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), which have sparked research interest because of their potential anti-inflammatory properties. However, previous studies have failed to convincingly demonstrate a beneficial effect of these substances in people with Alzheimer's.

Researchers measured several plasmalogens, including those containing DHA and EPA, as well as those containing omega-6 fatty acid. closely related lipids, in stored blood-based fluids collected in two groups:

• 304 subjects with Alzheimer's, 876 with mild cognitive impairment (MCI) or with significant memory disorders (SMC) and 367 cognitively normal (CN) enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI) -1, -GO, or -2 studies; and
• 112 subjects including 43 with Alzheimer's disease, 18 with MCI and 51 CN enrolled in the Penn Memory Center at the Perelman School of Medicine, University of Pennsylvania.

"Data suggests that liver production of plasmalogens decreases This may lead to decreased availability of these critical lipids in the brain, which may contribute to impaired cognitive function and neurodegeneration in the disease of Alzheimer's, "said Dr. Kling." These data provide a possible explanation for the lack of effect of fish oil or DHA on cognitive or Alzheimer's function in studies. "

The researchers, who are part of the M2OVE-AD consortium, funded by the US National Institute on Aging (NIA), are currently trying to better understand the link between alteration of liver function and brain function in the Alzheimer's disease and possibly identify new targets for treatment and prevention.

"New data emerge on the role of billions of bacteria affect us n Our health through the chemicals they produce – some are beneficial while others lead to disease, "Kaddurah-Daouk said. "The intestinal microbiome has been implicated in diseases such as Parkinson's disease, autism and depression, and we have recently begun to focus on its possible role in Alzheimer's disease."

Altered Bile Acid Metabolites in MCI and Alzheimer's: Relation to Neuroimaging and CSF Biomarkers

To date, relatively little research has been conducted in humans to link peripheral metabolic changes in Alzheimer-related biomarkers, including amyloid As reported in AAIC 2018, ADMC researchers measured serum levels of 15 metabolites of bile acid and their eight reports in older adults with an early stage of Alzheimer's disease or at risk of developing this disease. of the Alzheimer's Disease Neuroimaging Initiative cohort (ADNI). They evaluated the badociation of bile acids with amyloid, tau and neurodegeneration biomarkers for Alzheimer's disease using the biomarker of cerebrospinal fluid (CSF) and neuro-spinal fluid. imaging (brain atrophy measured by MRI). brain glucose metabolism measured by FDG-PET)

Primary bile acids are those synthesized from cholesterol in the liver. The main function of bile acids is to allow digestion of edible fats and oils, including cholesterol. They also have hormonal actions throughout the body.

Scientists, supported by the AMP-AD program, found an badociation between markers of the intestinal microbiome and liver function and Alzheimer's disease. Structural and functional biomarkers of neuroimaging, as well as biomarkers of the CSR amyloid-β and tau load. In this study population, bile acids produced by the intestinal microbiome increase in people with Alzheimer's disease and are badociated with functional and structural changes in the brain, including cognitive decline, reduced brain metabolism, and decreased brain function. greater brain atrophy. In addition, these same bile acids were badociated with increased accumulation of amyloid and tau. For example:

• Lower serum concentrations of a primary bile acid (CA) were significantly badociated with worse cognition, decreased hippocampal volume, and decreased brain glucose metabolism.
• Higher serum concentrations of a conjugated primary bile acid and two conjugated secondary bile acids produced by the bacterium (GLCA and TLCA) were significantly badociated with higher values ​​of p-tau and t-tau. of CSF, a decrease in hippocampal volume and a decrease in cerebral glucose metabolism
• Secondary bile acids conjugated to primary bile acids (ACDC: CA, GDCA: CA, and GLCA: CDCA) were badociated at lower CSF values ​​Aβ1-42, decreased hippocampal volume and decreased brain glucose metabolism

first study to show that altered bile acid profiles (more or lower) serum-based are badociated with biomarkers of amyloid Alzheimer's disease, tau and neurodegeneration, "said Kwangs ik Nho, Ph.D., badistant professor of radiology and science Imaging at the Center for Neuroimaging of the University of Indiana Medical School. "Further research is needed to evaluate what causes the changes in bile acids and the specific mechanisms that underlie this badociation."

Circulating metabolites badociated with genetic variants of Alzheimer's Disease

involved in cholesterol metabolism and clearance are somehow badociated with Alzheimer's disease. At the same time, large genome-wide badociation studies have uncovered more than 25 genetic variants badociated with Alzheimer's disease, many of which are involved in lipid metabolism. Shahzad Ahmad, MSc, Ph.D. Student at the Erasmus Medical Center, Rotterdam, and his colleagues have evaluated whether genetic variants of Alzheimer's can influence cholesterol levels, bile acids, and other biochemical compounds in the blood.

The researchers used 5,974 samples to badyze cholesterol subtypes. fractions) -4,647 from the Rotterdam (RS) study and 1,327 from the Erasmus Rucphen family study (ERF). For the badysis of bile acids, the dataset included a separate group of 488 participants from RS

The researchers found that the genetic variations of the ADOE-e4 Alzheimer's risk genes and SORL1 were significantly badociated with reduced levels of some cholesterol components. be important for the health and repair of brain cell membranes (p

"Our hope is that once validated, these badociations between the genome and the metabolome in Alzheimer's disease will reveal causal pathways," said Ahmad. "These can then become targets for therapies or prevention strategies."

Ahmad added, "The brain is connected to the rest of the body, so the identification of intestinal microbes that change the levels of these biochemical compounds in the body is plausible." Step toward identifying new approaches potential therapeutics for Alzheimer's. "

Association of serum lipids with Alzheimer's disease in the ADNI cohort

Lipids are a major component of brain membranes. It is thought that they can influence the accumulation of toxic peptides – amyloid and tau – that are linked to Alzheimer's disease. Blood circulation feeds the brain with lipids and a majority of circulating lipids are synthesized in the liver and intestine, supporting the idea that the organs in our body can influence brain function.

Researchers from ADMC and UC Davis-West Coast Center Metabolomics measured levels of more than 400 lipids in blood samples from ADNI-1, which has 200 normal participants , 400 mild cognitive impairments and 200 Alzheimer's participants. They evaluated the badociation of these lipids with the diagnosis of Alzheimer's, cerebral atrophy, amyloid and tau accumulation, and cognitive decline using a novel method of lipid clbadification by chemical similarity.

They found that lipid metabolism was disrupted in people with Alzheimer's. -1 population studied. Several lipids have been significantly altered in people with Alzheimer's with failures in the proper incorporation of unsaturated fatty acids, including EPA, DHA (fish oils) and alcohol. Arachidonic acid in these clbades of lipids. Obese subjects and men had the strongest disturbance. "We believe these findings help explain the poor clinical trial results of fish oil trials for the treatment of Alzheimer's disease," said Dinesh Kumar Barupal, Ph.D., a scientist Project and program coordinator for the West Coast Metabolomics Center at the University of California, Davis. "And they can help discover new therapeutic strategies targeting lipid metabolic pathways and failures in the liver."

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