Why is the New York Times

Can we go back to proving that drugs work in preventing, postponing, and ameliorating familial Alzheimer's disease (ad)? Ad is so devastating that there is a great public interest in the drug discovery process as evinced by the sheer number of articles in the serious popular press. The presently available, yet poorly performing, drugs have been approved despite their multiple peripheral side effects. The research on disease-modifying agents for the treatment of ad is largely focused on reducing amyloid plaques. However, it is now clear that companies and researchers alike are losing hope in finding an efficacious therapy rapidly that works in ad patients who are already cognitively impaired, and that people who staked their scientific and professional career on finding a cure for ad based on the amyloid hypothesis are shaken by the series of failed clinical trials within a short period of time. It is emerging that we may start to treat ad far too late to be able to make any significant slowing of the disease or postponing the onset of the symptoms of the disease. The history of drug development for other diseases should encourage us to focus on patients in whom we can identify the genetic markers associated with familial ad. Then when we have an efficacious and very safe drug, we will be able to establish its efficacy on, most importantly, cognition, but also at the level of plaques. This will provide the pharmacological evidence needed to show that it is worth fighting amyloidosis because it saves memory. We have a successful and lucrative history of preventive medicine on a large scale, all we need now is the foresight and will to switch strategy and no longer look for a magic bullet to fix ad, but to discover drugs that will delay and prevent the onset of ad, drugs that may be safely taken by symptom-free patients who are vulnerable and susceptible to ad. The initial population that might be preventatively treated against ad would indeed be those with genetic predisposition. While prevention trials are long and expensive as emphasized by the industry, the market for a safe and effective drug would be extended to the large number of patients susceptible to sporadic ad. Since the highest risk factor for sporadic ad is age, this would be an extraordinarily large market

Neuropeptides and pharmacology

The aim of the article is to briefly describe our work together with Dr. Viktor Mutt. He discovered and purified many new gastrointestinal bioactive neuropeptides that have important applications as therapeutic agents in diabetes, epilepsy, migraine and weight control. Dr. Muttâs strategy was to search for C­-terminally amidated peptides. We determined neuropeptide Y equilibrium binding for its receptor. Our work also included the L­-Ala scan of pharmacophores of the neuropeptide galanin (1­28). Finally, the work led to the establishment of the coexistence of peptides with small molecule neurotransmitters, such as serotonin, acetylcholine, noradrenaline and dopamine in central and peripheral neurons

Homophilic Interaction of Junctional Adhesion Molecule

Junctional adhesion molecule (JAM) is an integral membrane protein that belongs to the immunoglobulin superfamily, localizes at tight junctions, and regulates both paracellular permeability and leukocyte transmigration. To investigate molecular determinants of JAM function, the extracellular domain of murine JAM was produced as a recombinant soluble protein (rsJAM) in insect cells. rsJAM consisted in large part of noncovalent homodimers, as assessed by analytical ultracentrifugation. JAM dimers were also detected at the surface of Chinese hamster ovary cells transfected with murine JAM, as evaluated by cross-linking and immunoprecipitation. Furthermore, fluid-phase rsJAM bound dose-dependently solid-phase rsJAM, and such homophilic binding was inhibited by anti-JAM Fab BV11, but not by Fab BV12. Interestingly, Fab BV11 exclusively bound rsJAM dimers (but not monomers) in solution, whereas Fab BV12 bound both dimers and monomers. Finally, we mapped the BV11 and BV12 epitopes to a largely overlapping sequence in proximity of the extracellular amino terminus of JAM. We hypothesize that rsJAM dimerization induces a BV11-positive conformation which in turn is critical for rsJAM homophilic interactions. Dimerization and homophilic binding may contribute to both adhesive function and junctional organization of JAM

The role of inflammation in epilepsy.

Epilepsy is the third most common chronic brain disorder, and is characterized by an enduring predisposition to generate seizures. Despite progress in pharmacological and surgical treatments of epilepsy, relatively little is known about the processes leading to the generation of individual seizures, and about the mechanisms whereby a healthy brain is rendered epileptic. These gaps in our knowledge hamper the development of better preventive treatments and cures for the approximately 30% of epilepsy cases that prove resistant to current therapies. Here, we focus on the rapidly growing body of evidence that supports the involvement of inflammatory mediators-released by brain cells and peripheral immune cells-in both the origin of individual seizures and the epileptogenic process. We first describe aspects of brain inflammation and immunity, before exploring the evidence from clinical and experimental studies for a relationship between inflammation and epilepsy. Subsequently, we discuss how seizures cause inflammation, and whether such inflammation, in turn, influences the occurrence and severity of seizures, and seizure-related neuronal death. Further insight into the complex role of inflammation in the generation and exacerbation of epilepsy should yield new molecular targets for the design of antiepileptic drugs, which might not only inhibit the symptoms of this disorder, but also prevent or abrogate disease pathogenesis

A bloodâ based nutritional risk index explains cognitive enhancement and decline in the multidomain Alzheimer prevention trial

IntroductionMultinutrient approaches may produce more robust effects on brain health through interactive qualities. We hypothesized that a bloodâ based nutritional risk index (NRI) including three biomarkers of diet quality can explain cognitive trajectories in the multidomain Alzheimer prevention trial (MAPT) over 3â years.MethodsThe NRI included erythrocyte nâ 3 polyunsaturated fatty acids (nâ 3 PUFA 22:6nâ 3 and 20:5nâ 3), serum 25â hydroxyvitamin D, and plasma homocysteine. The NRI scores reflect the number of nutritional risk factors (0â 3). The primary outcome in MAPT was a cognitive composite Z score within each participant that was fit with linear mixedâ effects models.ResultsEighty percent had at lease one nutritional risk factor for cognitive decline (NRI â ¥1: 573 of 712). Participants presenting without nutritional risk factors (NRI=0) exhibited cognitive enhancement (β = 0.03 standard units [SU]/y), whereas each NRI point increase corresponded to an incremental acceleration in rates of cognitive decline (NRIâ 1: β = â 0.04 SU/y, P = .03; NRIâ 2: β = â 0.08 SU/y, P < .0001; and NRIâ 3: β = â 0.11 SU/y, P = .0008).DiscussionIdentifying and addressing these wellâ established nutritional risk factors may reduce ageâ related cognitive decline in older adults; an observation that warrants further study.Highlightsâ ¢Multiâ nutrient approaches may produce more robust effects through interactive propertiesâ ¢Nutritional risk index can objectively quantify nutritionâ related cognitive changesâ ¢Optimum nutritional status associated with cognitive enhancement over 3â yearsâ ¢Suboptimum nutritional status associated with cognitive decline over 3â yearsâ ¢Optimizing this nutritional risk index may promote cognitive health in older adultsPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152935/1/trc2jtrci201911004.pd

Reversal of Obesity and Insulin Resistance by a Non-Peptidic Glucagon-Like Peptide-1 Receptor Agonist in Diet-Induced Obese Mice

BACKGROUND: Glucagon-like peptide-1 (GLP-1) is recognized as an important regulator of glucose homeostasis. Efforts to utilize GLP-1 mimetics in the treatment of diabetes have yielded clinical benefits. A major hurdle for an effective oral therapy has been the difficulty of finding a non-peptidic GLP-1 receptor (GLP-1R) agonist. While its oral bioavailability still poses significant challenges, Boc5, one of the first such compounds, has demonstrated the attainment of GLP-1R agonism in diabetic mice. The present work was to investigate whether subchronic Boc5 treatment can restore glycemic control and induce sustainable weight loss in diet-induced obese (DIO) mice, an animal model of human obesity and insulin resistance. METHODOLOGY/PRINCIPAL FINDINGS: DIO mice were treated three times a week with Boc5 (0.3, 1 and 3 mg) for 12 weeks. Body weight, body mass index (BMI), food intake, fasting glucose, intraperitoneal glucose tolerance and insulin induced glucose clearance were monitored regularly throughout the treatment. Glucose-stimulated insulin secretion, β-cell mass, islet size, body composition, serum metabolic profiles, lipogenesis, lipolysis, adipose hypertrophy and lipid deposition in the liver and muscle were also measured after 12 weeks of dosing. Boc5 dose-dependently reduced body weight, BMI and food intake in DIO mice. These changes were associated with significant decreases in fat mass, adipocyte hypertrophy and peripheral tissue lipid accumulation. Boc5 treatment also restored glycemic control through marked improvement of insulin sensitivity and normalization of β-cell mass. Administration of Boc5 (3 mg) reduced basal but enhanced insulin-mediated glucose incorporation and noradrenaline-stimulated lipolysis in isolated adipocytes from obese mice. Furthermore, circulating leptin, adiponectin, triglyceride, total cholesterol, nonesterified fatty acid and high-density lipoprotein/low-density lipoprotein ratio were normalized to various extents by Boc5 treatment. CONCLUSIONS/SIGNIFICANCE: Boc5 may produce metabolic benefits via multiple synergistic mechanisms and may represent an attractive tool for therapeutic intervention of obesity and diabetes, by means of non-peptidic GLP-1R agonism

Why is the New York Times writing so much about Alzheimer’s disease therapies? TheScientificWorldJOURNAL 10, 1886–1889. This article should be cited as follows:

Can we go back to proving that drugs work in preventing, postponing, and ameliorating familial alzheimer&apos;s disease (ad)? Ad is so devastating that there is a great public interest in the drug discovery process as evinced by the sheer number of articles in the serious popular press. The presently available, yet poorly performing, drugs have been approved despite their multiple peripheral side effects. The research on disease-modifying agents for the treatment of ad is largely focused on reducing amyloid plaques. However, it is now clear that companies and researchers alike are losing hope in finding an efficacious therapy rapidly that works in ad patients who are already cognitively impaired, and that people who staked their scientific and professional career on finding a cure for ad based on the amyloid hypothesis are shaken by the series of failed clinical trials within a short period of time. It is emerging that we may start to treat ad far too late to be able to make any significant slowing of the disease or postponing the onset of the symptoms of the disease. The history of drug development for other diseases should encourage us to focus on patients in whom we can identify the genetic markers associated with familial ad. Then when we have an efficacious and very safe drug, we will be able to establish its efficacy on, most importantly, cognition, but also at the level of plaques. This will provide the pharmacological evidence needed to show that it is worth fighting amyloidosis because it saves memory. We have a successful and lucrative history of preventive medicine on a large scale, all we need now is the foresight and will to switch strategy and no longer look for a magic bullet to fix ad, but to discover drugs that will delay and prevent the onset of ad, drugs that may be safely taken by symptom-free patients who are vulnerable and susceptible to ad. The initial population that might be preventatively treated against ad would indeed be those with genetic predisposition. While prevention trials are long and expensive as emphasized by the industry, the market for a safe and effective drug would be extended to the large number of patients susceptible to sporadic ad. Since the highest risk factor for sporadic ad is age, this would be an extraordinarily large market