New research presented today at the Society for Neuroscience’s annual conference, Neuroscience (Washington DC, USA; 11–15 November 2017), has indicated a role for the microbiome in neurodegenerative disease and pointed towards new treatments for Parkinson’s and Alzheimer’s diseases (PD and AD, respectively).
Speaking about five key studies highlighted by the Society (summarized below), Tracy Bale (University of Maryland School of Medicine, MD, USA) said: “The results presented today add to the growing body of evidence showing the influence of the gut on the brain and the crucial relationship between the two. Targeting the gut introduces a different and promising angle to tackle brain disorders across the lifespan.”
Gut-derived compounds may block protein misfolding
Research presented by Lap Ho (Icahn School of Medicine at Mount Sinai, NY, USA) and colleagues has linked gut microbiota metabolism with protective mechanisms against Parkinson’s-plus syndromes. In their study, the team tested six gut-derived metabolites, GMP10, GMP11, GMP26, GMP28, GMP39, and GMP44, and identified three of these – GMP26, GMP44 and GMP28 – that inhibited aggregation of alpha-synuclein in vitro. They then extended their experiments in vivo to a Drosophila model of PD (C9orf72 gene mutation) with age-dependent photoreceptor neurodegeneration, finding that all six of the compounds reduced degeneration when given as a food supplement, with two of the metabolites almost completely preventing degeneration.
Ho concluded: “Our new evidence suggests the feasibility of developing gut microbiota-derived compounds to simultaneously target both alpha-synuclein misfolding and C9orf72 gene mutation to increase the likelihood of therapeutic efficacy.”
Parkinson’s rat model exhibits elevated gut inflammation
In a pilot study, researchers examined colon tissue from 10 control rats and 12 PD model rats (models exposed to BSSG toxin to induce PD-like symptoms). All PD rats had elevated levels of the inflammatory marker CD68, compared with just one control rat.
“Inflammation in the lining of the gut may be indicative of Parkinson’s disease development as much as brain inflammation,” said senior author Doris Doudet (University of British Columbia, Canada). “This study is a first step to map the progression of inflammation in the gut along the timeline of the development of other neurodegenerative disease-related symptoms in a new progressive animal model.”
Parkinson’s pathology spreads from brain to gut in nonhuman primates
New research has indicated that alpha-synuclein may spread from the brain to gut in PD, adding to previous research that suggested the protein spreads in the opposite direction, from brain to gut.
To test whether alpha-synuclein can spread from both brain to gut and gut to brain, the research team injected Lewy bodies derived from PD patients into the stomachs of one group of baboons, and into the brains of another group. Two years later, the brains and small intestines of these animals were examined for neuronal death and alpha-synuclein pathology. Regardless of the site of injection, the animals had lesions and pathology in both brain and gut.
“The findings from this study establish that alpha-synuclein species might move up and down the neural axis in nonhuman primates,” said senior author Erwan Bezard (Institute of Neurodegenerative Diseases, France). “Although moving up was expected, it is the first demonstration in primates. Moving down is totally unexpected and groundbreaking.”
Alzheimer’s-related gene affects gut microbiome in mice
In a study aiming to determine whether APOE affects the gut microbiome, researchers examined mice expressing APOE2, APOE3, or APOE4 alleles. Sequencing DNA isolated from fecal samples revealed the populations of bacteria living in the animals’ guts. The bacterial populations varied significantly between mice expressing APOE2, APOE3, or APOE4 alleles; for example, bacteria from the Ruminococcaceae family were most abundant in APOE2 mice and the least abundant in APOE4 mice.
“These results suggest that APOE alleles may differentially affect the gut microbiome, which could contribute to the actions of APOE in modulating AD risk,” said lead author Ishita Parikh (University of Kentucky, KY, USA). “Since the gut microbiome may be manipulated by factors such as probiotics and antibiotics, this study may lead to novel ways to reduce the risk of AD.”
Memory deficits reduced by probiotics in AD mouse model
In a study aiming to determine whether probiotics can slow AD progression, researchers fed AD model mice and control mice either a probiotic-supplemented diet or a normal diet for 2 months. AD mice on a normal diet exhibited increased memory deficits compared with control mice, but AD mice fed the probiotic showed improved memory. In addition, AD mice were observed to have leakier guts, which was corrected with probiotic treatment.
“Our study suggests that gut bacteria can contribute to the pathological features associated with Alzheimer’s disease and that probiotic supplementation can help to slow down the progression of disease,” said lead author Harpreet Kaur (University of North Dakota, ND, USA). “This is exciting news because probiotics are widely available in the form of foods and food supplements.”
Source: Society for Neuroscience