Pathology of the Aging Brain in Domestic and Laboratory Animals, and Animal Models of Human Neurodegenerative Diseases

Pesticides are routinely screened in studies that follow specific guidelines for possible neuropathogenicity in laboratory animals. These tests will detect chemicals that are by themselves strong inducers of neuropathogenesis if the tested strain is susceptible relative to the time of administration and methodology of assessment. Organophosphate induced delayed neuropathy (OPIDN) is the only known human neurodegenerative disease associated with pesticides and the existing study guidelines with hens are a standard for predicting the potential for organophosphates to cause OPIDN. Although recent data have led to the suggestion that pesticides may be risk factors for Parkinsonism syndrome, there are no specific protocols to evaluate this syndrome in the existing study guidelines. Ideally additional animal models for human neurodegenerative diseases need to be developed and incorporated into the guidelines to further assure the public that limited exposure to pesticides is not a risk factor for neurodegenerative diseases.

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Is There a Brain Microbiome?

Neuroscience Insights ◽

10.1177/26331055211018709 ◽

2021 ◽

Vol 16 ◽

pp. 263310552110187

Author(s):

Christopher D Link

Keyword(s):

Animal Models ◽

Human Brain ◽

Neurodegenerative Diseases ◽

Ground Truth ◽

Healthy Human ◽

Strong Motivation ◽

The Many ◽

The Brain

Numerous studies have identified microbial sequences or epitopes in pathological and non-pathological human brain samples. It has not been resolved if these observations are artifactual, or truly represent population of the brain by microbes. Given the tempting speculation that resident microbes could play a role in the many neuropsychiatric and neurodegenerative diseases that currently lack clear etiologies, there is a strong motivation to determine the “ground truth” of microbial existence in living brains. Here I argue that the evidence for the presence of microbes in diseased brains is quite strong, but a compelling demonstration of resident microbes in the healthy human brain remains to be done. Dedicated animal models studies may be required to determine if there is indeed a “brain microbiome.”

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Emerging hiPSC Models for Drug Discovery in Neurodegenerative Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms22158196 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8196

Author(s):

Dorit Trudler ◽

Swagata Ghatak ◽

Stuart A. Lipton

Keyword(s):

Drug Discovery ◽

Animal Models ◽

Neurodegenerative Diseases ◽

Disease Modeling ◽

Induced Pluripotent Stem Cell ◽

Neural Function ◽

Neural Cells ◽

Human Samples ◽

Healthy Donors ◽

Induced Pluripotent

Neurodegenerative diseases affect millions of people worldwide and are characterized by the chronic and progressive deterioration of neural function. Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD), represent a huge social and economic burden due to increasing prevalence in our aging society, severity of symptoms, and lack of effective disease-modifying therapies. This lack of effective treatments is partly due to a lack of reliable models. Modeling neurodegenerative diseases is difficult because of poor access to human samples (restricted in general to postmortem tissue) and limited knowledge of disease mechanisms in a human context. Animal models play an instrumental role in understanding these diseases but fail to comprehensively represent the full extent of disease due to critical differences between humans and other mammals. The advent of human-induced pluripotent stem cell (hiPSC) technology presents an advantageous system that complements animal models of neurodegenerative diseases. Coupled with advances in gene-editing technologies, hiPSC-derived neural cells from patients and healthy donors now allow disease modeling using human samples that can be used for drug discovery.

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Prebiotics, immune function, infection and inflammation: a review of the evidence

British Journal Of Nutrition ◽

10.1017/s0007114508055608 ◽

2008 ◽

Vol 101 (5) ◽

pp. 633-658 ◽

Cited By ~ 143

Author(s):

Amy R. Lomax ◽

Philip C. Calder

Keyword(s):

Animal Models ◽

Immune Function ◽

Intestinal Inflammation ◽

Adaptive Immune System ◽

Laboratory Animals ◽

Beneficial Effects ◽

Inflammatory Conditions ◽

Intestinal Infections ◽

Inflammatory Processes ◽

Irritable Bowel

β2-1 Fructans are carbohydrate molecules with prebiotic properties. Through resistance to digestion in the upper gastrointestinal tract, they reach the colon intact, where they selectively stimulate the growth and/or activity of beneficial members of the gut microbiota. Through this modification of the intestinal microbiota, and by additional mechanisms, β2-1 fructans may have beneficial effects upon immune function, ability to combat infection, and inflammatory processes and conditions. In this paper, we have collated, summarised and evaluated studies investigating these areas. Twenty-one studies in laboratory animals suggest that some aspects of innate and adaptive immunity of the gut and the systemic immune systems are modified by β2-1 fructans. In man, two studies in children and nine studies in adults indicate that the adaptive immune system may be modified by β2-1 fructans. Thirteen studies in animal models of intestinal infections conclude a beneficial effect of β2-1 fructans. Ten trials involving infants and children have mostly reported benefits on infectious outcomes; in fifteen adult trials, little effect was generally seen, although in specific situations, certain β2-1 fructans may be beneficial. Ten studies in animal models show benefit of β2-1 fructans with regard to intestinal inflammation. Human studies report some benefits regarding inflammatory bowel disease (four positive studies) and atopic dermatitis (one positive study), but findings in irritable bowel syndrome are inconsistent. Therefore, overall the results indicate that β2-1 fructans are able to modulate some aspects of immune function, to improve the host's ability to respond successfully to certain intestinal infections, and to modify some inflammatory conditions.

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New Approaches to Profile the Microbiome for Treatment of Neurodegenerative Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-210198 ◽

2021 ◽

pp. 1-29

Author(s):

David R. Elmaleh ◽

Matthew A. Downey ◽

Ljiljana Kundakovic ◽

Jeremy E. Wilkinson ◽

Ziv Neeman ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Neurodegenerative Disease ◽

Gut Microbiome ◽

Treatment Options ◽

Treatment Strategies ◽

Modern Society ◽

Aging Brain ◽

New Approaches ◽

Microbiome Profile ◽

Carry Over

Progressive neurodegenerative diseases represent some of the largest growing treatment challenges for public health in modern society. These diseases mainly progress due to aging and are driven by microglial surveillance and activation in response to changes occurring in the aging brain. The lack of efficacious treatment options for Alzheimer’s disease (AD), as the focus of this review, and other neurodegenerative disorders has encouraged new approaches to address neuroinflammation for potential treatments. Here we will focus on the increasing evidence that dysbiosis of the gut microbiome is characterized by inflammation that may carry over to the central nervous system and into the brain. Neuroinflammation is the common thread associated with neurodegenerative diseases, but it is yet unknown at what point and how innate immune function turns pathogenic for an individual. This review will address extensive efforts to identify constituents of the gut microbiome and their neuroactive metabolites as a peripheral path to treatment. This approach is still in its infancy in substantive clinical trials and requires thorough human studies to elucidate the metabolic microbiome profile to design appropriate treatment strategies for early stages of neurodegenerative disease. We view that in order to address neurodegenerative mechanisms of the gut, microbiome and metabolite profiles must be determined to pre-screen AD subjects prior to the design of specific, chronic titrations of gut microbiota with low-dose antibiotics. This represents an exciting treatment strategy designed to balance inflammatory microglial involvement in disease progression with an individual’s manifestation of AD as influenced by a coercive inflammatory gut.

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Neuroendocrine modulation of the “menopause”: insights into the aging brain

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1999.277.6.e965 ◽

1999 ◽

Vol 277 (6) ◽

pp. E965-E970 ◽

Cited By ~ 6

Author(s):

Phyllis M. Wise

Keyword(s):

Animal Models ◽

Ovarian Follicles ◽

Physiological Change ◽

Menopausal Transition ◽

Aging Brain ◽

Neural Signals ◽

Present Evidence ◽

The Brain

The menopause marks the permanent end of fertility in women. It was once thought that this dramatic physiological change could be explained simply by the exhaustion of the reservoir of ovarian follicles. New data from studies performed in women and animal models make us reassess this assumption. An increasing body of evidence suggests that there are multiple pacemakers that contribute to the transition to irregular cycles, decreasing fertility, and the timing of the menopause. We will present evidence that lends credence to the possibility that a dampening and desynchronization of the precisely orchestrated neural signals lead to miscommunication between the brain and the pituitary-ovarian axis, and that this constellation of hypothalamic-pituitary-ovarian events leads to the deterioration of regular cyclicity and heralds menopausal transition.

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Developments and new vistas in the field of melanocortins

BioMolecular Concepts ◽

10.1515/bmc-2015-0023 ◽

2015 ◽

Vol 6 (5-6) ◽

pp. 361-382 ◽

Cited By ~ 4

Author(s):

Sheila Leone ◽

Giorgio Noera ◽

Alfio Bertolini

Keyword(s):

Animal Models ◽

Neurodegenerative Diseases ◽

Sexual Activity ◽

Ischemia Reperfusion ◽

Gouty Arthritis ◽

Traumatic Injury ◽

Large Body ◽

Hypovolemic Shock ◽

Therapeutic Effects ◽

Tissue Ischemia

AbstractMelanocortins play a fundamental role in several basic functions of the organism (sexual activity, feeding, inflammation and immune responses, pain sensitivity, response to stressful situations, motivation, attention, learning, and memory). Moreover, a large body of animal data, some of which were also confirmed in humans, unequivocally show that melanocortins also have impressive therapeutic effects in several pathological conditions that are the leading cause of mortality and disability worldwide (hemorrhagic, or anyway hypovolemic, shock; septic shock; respiratory arrest; cardiac arrest; ischemia- and ischemia/reperfusion-induced damage of the brain, heart, intestine, and other organs; traumatic injury of brain, spinal cord, and peripheral nerves; neuropathic pain; toxic neuropathies; gouty arthritis; etc.). Recent data obtained in animal models seem to moreover confirm previous hypotheses and preliminary data concerning the neurotrophic activity of melanocortins in neurodegenerative diseases, in particular Alzheimer’s disease. Our aim was (i) to critically reconsider the established extrahormonal effects of melanocortins (on sexual activity, feeding, inflammation, tissue hypoperfusion, and traumatic damage of central and peripheral nervous system) at the light of recent findings, (ii) to review the most recent advancements, particularly on the effects of melanocortins in models of neurodegenerative diseases, (iii) to discuss the reasons that support the introduction into clinical practice of melanocortins as life-saving agents in shock conditions and that suggest to verify in clinical setting the impressive results steadily obtained with melanocortins in different animal models of tissue ischemia and ischemia/reperfusion, and finally, (iv) to mention the advisable developments, particularly in terms of selectivity of action and of effects.

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A fiber-deprived diet causes cognitive impairment and hippocampal microglia-mediated synaptic loss through the gut microbiota and metabolites

Microbiome ◽

10.1186/s40168-021-01172-0 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Hongli Shi ◽

Xing Ge ◽

Xi Ma ◽

Mingxuan Zheng ◽

Xiaoying Cui ◽

...

Keyword(s):

Cognitive Impairment ◽

Gut Microbiota ◽

Neurodegenerative Diseases ◽

Dietary Fiber ◽

Brain Aging ◽

Synaptic Proteins ◽

Aging Brain ◽

Normal Brain ◽

Fiber Intake ◽

Synaptic Ultrastructure

Abstract Background Cognitive impairment, an increasing mental health issue, is a core feature of the aging brain and neurodegenerative diseases. Industrialized nations especially, have experienced a marked decrease in dietary fiber intake, but the potential mechanism linking low fiber intake and cognitive impairment is poorly understood. Emerging research reported that the diversity of gut microbiota in Western populations is significantly reduced. However, it is unknown whether a fiber-deficient diet (which alters gut microbiota) could impair cognition and brain functional elements through the gut-brain axis. Results In this study, a mouse model of long-term (15 weeks) dietary fiber deficiency (FD) was used to mimic a sustained low fiber intake in humans. We found that FD mice showed impaired cognition, including deficits in object location memory, temporal order memory, and the ability to perform daily living activities. The hippocampal synaptic ultrastructure was damaged in FD mice, characterized by widened synaptic clefts and thinned postsynaptic densities. A hippocampal proteomic analysis further identified a deficit of CaMKIId and its associated synaptic proteins (including GAP43 and SV2C) in the FD mice, along with neuroinflammation and microglial engulfment of synapses. The FD mice also exhibited gut microbiota dysbiosis (decreased Bacteroidetes and increased Proteobacteria), which was significantly associated with the cognitive deficits. Of note, a rapid differentiating microbiota change was observed in the mice with a short-term FD diet (7 days) before cognitive impairment, highlighting a possible causal impact of the gut microbiota profile on cognitive outcomes. Moreover, the FD diet compromised the intestinal barrier and reduced short-chain fatty acid (SCFA) production. We exploit these findings for SCFA receptor knockout mice and oral SCFA supplementation that verified SCFA playing a critical role linking the altered gut microbiota and cognitive impairment. Conclusions This study, for the first time, reports that a fiber-deprived diet leads to cognitive impairment through altering the gut microbiota-hippocampal axis, which is pathologically distinct from normal brain aging. These findings alert the adverse impact of dietary fiber deficiency on brain function, and highlight an increase in fiber intake as a nutritional strategy to reduce the risk of developing diet-associated cognitive decline and neurodegenerative diseases.

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