The GRK2 Overexpression Is a Primary Hallmark of Mitochondrial Lesions during Early Alzheimer Disease

Increasing evidence points to vascular damage as an early contributor to the development of two leading causes of age-associated dementia, namely Alzheimer disease (AD) and AD-like pathology such as stroke. This review focuses on the role of G protein-coupled receptor kinases (GRKs) as they relate to dementia and how the cardio and cerebrovasculature is involved in AD pathogenesis. The exploration of GRKs in AD pathogenesis may help bridge gaps in our understanding of the heart-brain connection in relation to neurovisceral damage and vascular complications of AD. The a priori basis for this inquiry stems from the fact that kinases of this family regulate numerous receptor functions in the brain, myocardium and elsewhere. The aim of this review is to discuss the finding of GRK2 overexpression in the context of early AD pathogenesis. Also, we consider the consequences for this overexpression as a loss of G-protein coupled receptor (GPCR) regulation, as well as suggest a potential role for GPCRs and GRKs in a unifying theory of AD pathogenesis through the cerebrovasculature. Finally, we synthesize this newer information in an attempt to put it into context with GRKs as regulators of cellular function, which makes these proteins potential diagnostic and therapeutic targets for future pharmacological intervention

Leaky Gut, Leaky Brain?

‘Leaky gut’ syndrome, long-associated with celiac disease, has attracted much attention in recent years and for decades, was widely known in complementary/alternative medicine circles. It is often described as an increase in the permeability of the intestinal mucosa, which could allow bacteria, toxic digestive metabolites, bacterial toxins, and small molecules to ‘leak’ into the bloodstream. Nervous system involvement with celiac disease is know to occur even at subclinical levels. Gluten and gluten sensitivity are considered to trigger this syndrome in individuals genetically predisposed to celiac disease. However, the incidence of celiac disease in the general population is quite low. Nevertheless, increased public interest in gluten sensitivity has contributed to expanded food labels stating ‘gluten-free’ and the proliferation of gluten-free products, which further drives gluten-free lifestyle changes by individuals without frank celiac disease. Moreover, systemic inflammation is associated with celiac disease, depression, and psychiatric comorbidities. This mini-review focuses on the possible neurophysiological basis of leaky gut; leaky brain disease; and the microbiota’s contribution to inflammation, gastrointestinal, and blood-brain barrier integrity, in order to build a case for possible mechanisms that could foster further ‘leaky’ syndromes. We ask whether a gluten-free diet is important for anyone or only those with celiac disease

Leaky Gut, Leaky Brain?

‘Leaky gut’ syndrome, long-associated with celiac disease, has attracted much attention in recent years and for decades, was widely known in complementary/alternative medicine circles. It is often described as an increase in the permeability of the intestinal mucosa, which could allow bacteria, toxic digestive metabolites, bacterial toxins, and small molecules to ‘leak’ into the bloodstream. Nervous system involvement with celiac disease is know to occur even at subclinical levels. Gluten and gluten sensitivity are considered to trigger this syndrome in individuals genetically predisposed to celiac disease. However, the incidence of celiac disease in the general population is quite low. Nevertheless, increased public interest in gluten sensitivity has contributed to expanded food labels stating ‘gluten-free’ and the proliferation of gluten-free products, which further drives gluten-free lifestyle changes by individuals without frank celiac disease. Moreover, systemic inflammation is associated with celiac disease, depression, and psychiatric comorbidities. This mini-review focuses on the possible neurophysiological basis of leaky gut; leaky brain disease; and the microbiota’s contribution to inflammation, gastrointestinal, and blood-brain barrier integrity, in order to build a case for possible mechanisms that could foster further ‘leaky’ syndromes. We ask whether a gluten-free diet is important for anyone or only those with celiac disease

Dysautonomia in Autism Spectrum Disorder: Case Reports of a Family with Review of the Literature

Case histories of a mother and her two children are reported. The mother was a recovered alcoholic. She and her two children, both of whom had symptoms that are typical of autistic spectrum disorder, had dysautonomia. All had intermittently abnormal erythrocyte transketolase studies indicating abnormal thiamine pyrophosphate homeostasis. Both children had unusual concentrations of urinary arsenic. All had symptomatic improvement with diet restriction and supplementary vitamin therapy but quickly relapsed after ingestion of sugar, milk, or wheat. The stress of a heavy metal burden, superimposed on existing genetic or epigenetic risk factors, may be important in the etiology of autism spectrum disorder when in combination. Dysautonomia has been associated with several diseases, including autism, without a common etiology. It is hypothesized that oxidative stress results in loss of cellular energy and causes retardation of hard wiring of the brain in infancy, affecting limbic system control of the autonomic nervous system

Involvement of Maillard Reactions in Alzheimer Disease

Maillard reactions have been explored by food chemists for many years. It is only recently that the advanced glycation end products (AGEs), the end products of the Maillard reaction, have been detected in a wide variety of diseases such as diabetes, atherosclerosis, cataractogenesis, Parkinson disease and Alzheimer disease (AD). In this review, we discuss the chemistry and biochemistry of AGE-related crosslinks such as pyrraline, pentosidine, carboxymethyllysine (CML), crosslines, imidazolidinones, and dilysine crosslinks (GOLD and MOLD), as well as their possible involvement in neurodegenerative conditions. Pentosidine and CML are found in elevated amounts in the major lesions of the AD brain. Glycation is also implicated in the formation of the paired helical filaments (PHF), a component of the neurofibrillary tangles (NFTs). Amyloid-ß peptide and proteins of the cerebrospinal fluid are also glycated in patients with AD. In order to ameliorate the effects of AGEs on AD pathology, various inhibitors of AGEs have been increasingly explored. It is hoped that understanding of the mechanism of the AGEs formation and their role in the neurodegeneration will result in novel therapeutics for neuroprotection

The Role of Polyphenolic Antioxidants in Health, Disease, and Aging

Polyphenolic antioxidants from dietary sources are frequently a topic of interest due to widespread scientific agreement that they may help lower the incidence of certain cancers, cardiovascular and neurodegenerative diseases, and DNA damage and even may have antiaging properties. On the other hand, questions still remain as to whether some antioxidants could be potentially harmful to health, because an increase in glycation-mediated protein damage (carbonyl stress) has been reported in some cases. Nevertheless, the quest for healthy aging has led to the extensive use of phytochemically derived antioxidants to disrupt age-associated deterioration in physiological function and to prevent many age-related diseases. Although a diet rich in the polyphenolic forms of antioxidants does seem to offer hope in delaying the onset of age-related disorders, it is still too early to define their exact clinical benefit for treating age-related disease. This review critically examines polyphenolic antioxidants, such as flavonoids, curcumene, and resveratrol in health, disease, and aging with the hope that a better understanding of the many mechanisms involved with these diverse compounds may lead to better health and novel treatment approaches for age-related diseases

Alzheimer Disease: A New Beginning or a Final Exit?

Today, a new chapter is being written in the book of Alzheimer disease, one that is challenging the longstanding view that adult neurons are incapable of division, remain nonproliferative, and are terminally differentiated. Here, we review the provocative notion that, in Alzheimer disease, whole populations of nonstem cell neurons leave their quiescent state and re-enter into the cell cycle. However, such neuronal re-entry into the cell cycle is futile and ultimately leads to the neurodegeneration that typifies Alzheimer disease.Fil: Obrenovich, Mark E.. No especifíca;Fil: Raina, Arun K.. No especifíca;Fil: Ogawa, Osamu. No especifíca;Fil: Atwood, Craig S.. No especifíca;Fil: Morelli, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Smith, Mark A.. No especifíca