Frontiers in Anti-Infective Drug Discovery: Volume 6 E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Fachliteratur
- Serie: Frontiers in Anti-Infective Drug Discovery
- Sprache: Englisch
This book series brings updated reviews to readers interested in advances in the development of anti-infective drug design and discovery. The scope of the book series covers a range of topics including rational drug design and drug discovery, medicinal chemistry, in-silico drug design, combinatorial chemistry, high-throughput screening, drug targets, recent important patents, and structure-activity relationships.
Frontiers in Anti-Infective Drug Discovery is a valuable resource for pharmaceutical scientists and post-graduate students seeking updated and critically important information for developing clinical trials and devising research plans in this field.
The sixth volume of this series features 6 chapters that cover the following topics:
- Alternative anti-infective / anti-inflammatory therapeutic options for fighting Alzheimer’s disease
- Microbial peptides that combat microbial biofilms
- Malaria and its treatment
- Tuberculosis drugs
… and much more.
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Veröffentlichungsjahr: 2017
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Frontiers in Anti-Infective Drug Discovery
(Volume 6)
Edited By
Atta-ur-Rahman, FRS
&
M. Iqbal Chaudhary
BENTHAM SCIENCE PUBLISHERS LTD
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PREFACE
Infections kill more people than all other diseases combined. Despite the tremendous development in this field, infections are increasingly difficult to treat today because of the development of organisms resistant to antibiotics. Human sufferings because of bacterial, fungal, parasitic, and viral infections are therefore likely to increase many fold in the new future. Emerging antibiotic resistance in all infection-causing microorganisms is making many believe that the era of antibiotics is coming to an end. Recent reports establish that the chances of dying from hospital-acquired pneumonia or septicaemia are much higher from drug-resistant infections. In this context, extensive research, both in academia and in pharmaceutical industries, has begun, covering various aspects of this complex topic, such as infection biology, genomics of resistance, new drug target identification, and search for new antibiotics. It is often difficult, even for a prolific reader, to keep pace with these exciting developments. Thus, the need of a comprehensive book review series is greatly felt. The present series of volumes, partly addresses this need.
The last five volumes of the ebook series “Frontiers in Anti-Infective Drug Discovery” have attracted great scientific interest, as a welcome addition to the global literature in this active area of research. The present volume of this internationally recognized books series comprises of six carefully selected reviews on various aspects of infection, etiology, and treatment, contributed by leading experts in this field. Each review is focused on important aspects of anti-infection drug discovery and development, based on various innovative approaches, including relationship between infections and neurological disorders, identification of new molecular targets, outcomes of pre-clinical and clinical studies on new and novel classes of antimicrobial and antiviral drugs, combination therapies, and strategies to overcome emerging antibiotic resistance.
Pantazaki et al., have reviewed some of the most striking recent reports on the relationship of infectious and inflammatory etiology with the on-set of Alzheimer’s diseases (AD). Recent research has shown that many microorganisms, such as bacteria (Helicobacter pylori), viruses (Herpes simplex virus, influenza, CMV, etc.) and fungi can cause AD. It has been reported that these microorganisms and viruses can cross the blood brain membrane and cause mild to severe infections in the brain. Persistent or acute neuronal and peripheral inflammatory response against these infectious agents lead to accumulation of amyloid protein aggregates which are the major cause of AD. It has also been reported that an alternation in normal gut microbiota can cause the accumulation of functional amyloid proteins which are then transported to the Central Nervous System (CNS) causing neurologic and psychiatric disorders, such as schizophrenia, anxiety, and AD. The review provides an interesting description of the effects of chronic inflammatory responses against immune-reactive proteins as risk factors for nervous system disorders. The authors have also recommended the consumption of natural products and natural diets, such as Mediterranean and Asian diets, which are capable of preventing AD or reducing the risk of AD, and strengthening the body’s ability to confront infections. In brief, this review is a comprehensive commentary based on recent literature on the possible relationship between the infection, microbiota and the on-set of Alzheimer’s diseases. The authors thus support the use of chemotherapeutic and dietary approaches for the prevention of AD.
The review contributed by Dwivedi et al., focuses on the conventional and current treatments of malaria comprising of natural substances and synthetic analogues. The choice of therapeutic agents against malaria depends on the species of parasite, the pattern of resistance, and the seriousness of the infection. Despite major developments in the understanding of the aetiology of malaria at the molecular level, and the introduction of new drugs, the disease is causing considerable morbidity and mortality in Asia, South America, and Sub-Saharan Africa. According the WHO, malaria kills more people world-wide than all other parasitic diseases taken together. The emergence and spread of multidrug resistant strains of malarial parasites have further limited the choice of antimalarial chemotherapeutics. This highlights the urgent need of efficient research for developing newer and broad spectrum antimalarial drugs. The development of an effective malaria vaccines has remained a major challenge for scientists, with only limited success achieved so far. This review highlights the importance of the development of new drug delivery systems which maximize the on-site effect and minimize the adverse effects of existing antimalarial drugs. Recent development of nanoparticles as careers for malaria chemotherapy which can minimize the side effects and improve bioavailability and selectivity of the drugs has also been discussed in this review. The authors have emphasized the need for continuous search for antimalarial drugs, giving the example of arteether (ART) and bulaquin. The review provides a comprehensive account of challenges and opportunities in malarial chemotherapy, and proposes several directions for future research in this important field.
Zehra Küçükbay and Hasan Küçükbay have contributed a chapter on recent developments in the field of novel antibiotics and antimicrobial agents. Their review presents merits and demerits of various classes of antibiotics, such as b-lactams, macrolides, fluoroquinolones, tetracyclines, and aminoglycosides, in the context of emerging resistance against them. The authors have focused on natural products as possible antimalarial agents which can circumvent the emerging resistance issues while having limited side-effects. By providing examples of fascinating natural products used against infections such as aspirin (willow plant), opioids (opium poppy), atropine (Atropa belladonna), and quinine (cinchona), the authors have advocated the need for searching natural chemical diversity as a source of new antimicrobial and resistance-reversal agents against increasingly resistant infections. This review thus provides an in-depth look at the most significant developments in antimalarial drug development and prospects of natural products as sources of new antimalarial drugs.
Tuberculosis or TB is among the most serious infectious diseases that can affect almost any tissue of the body, especially the lungs. Once considered to be a disease of the developing world, TB has recently emerged in the developed world as a co-infection along with HIV, since people with a compromised immune system develop TB very quickly. Many strains of Mycobacterium have now developed resistance against the arsenal of available drugs, making the treatment increasingly difficult. TB patients are now required to take several types of medications for long durations to eradicate the infection, prevent relapse, and avoid the development of antibiotic resistance. Recently two drugs, Bedaquiline and Delamanid, have received conditional approvals for the treatment of MDR-TB, for patients where other treatments fail. Jawed Ahsan has reviewed the recent developments in the TB chemotherapy, including new and repurposed antitubercular drugs in advanced phases of clinical trials. He has also commented on various vaccine candidates which are in clinical development. The review also discusses the need of new diagnostics, and anti-TB drugs as well as TB vaccines to control the spread of TB pandemic in the developing and the developed world.
Naseem Ahmed has contributed a review on widespread hepatitis viral infectious disease and its treatment. Hepatitis is wide spread, particularly in the poor regions of the world. Various forms of the hepatitis virus (hepatitis A- E) are wreaking havoc to many the health care systems of the developing world. Among the various forms, hepatitis A, B, C, D, and E are the most common. Over a billion people are estimated to be either patients or carrier of hepatitis. Cases of non-viral, and autoimmune hepatitis are widely reported due to alcohol consumption, use of medications against chronic disorders, and spread of autoimmune diseases. Current treatment options are often expensive, and beyond the reach of poor patients. However recent developments in this field have been very promising. Interferons alone or pegylated interferons have been used with 35-40% success, and numerous side effects. New medicines which target NS3/4A protease, NS5B polymerase, and NS5A enzymes have been developed with phenomenal success of 70-90%. Several other inhibitors of NS5B and NS5A polymerase targets are in various stages of development. The chapter provides an excellent review of the recent literature on new antiviral drug development, identification of new targets, investigational and novel therapies and most importantly merits and demerits of existing anti-hepatitis medicines.
Finally, the review by Shukla et al., is focused on the discovery and development of various classes of natural and synthetic peptides and polypeptides as novel anti-infective agents as well as structure -function relationships. The emergence of resistance has led to the development of non-classical antibiotics, including peptide antibiotics, especially cationic peptides. Several thousands of such peptides have been isolated from natural sources (plants, animals, microbial, etc), and many more have been synthesized. However only a few have entered into clinical trials. As antimicrobial peptides (AMPs) kill bacteria quickly by the physical disruption of cell membranes, the emergence of resistance against them is less likely. The authors have also discussed various aspects of uses of AMPs, including their possible use as delivery vectors to transport the cell impermeable drugs to the cell interior. Their diverse and broad spectrum antimicrobial activity has been described in literature. These peptides offer a potentially rich source of novel antimicrobial agents. The authors have presented numerous examples of AMPs along with reports of modifications in the existing peptides, isolation of novel peptides from nature, the introduction of non-natural amino acids in their structures, and their mechanisms of action.
We are pleased to express our gratitude to all the authors of the above cited reviews for their excellent scholarly contributions to the 6th volume of this ebook series. We also appreciate the efforts of the brilliant publication team of Bentham Science Publishers for the efficient processing of the treatise. The skills and efforts of Ms. Fariya Zulfiqar (Assistant Manager Publications) & Mr. Shehzad Naqvi (Manager Publications), and excellent management of Mr. Mahmood Alam (Director Publications) are greatly appreciated. We also hope that like the previous volumes of this internationally recognized book series, the current volume will also receive a wide readership from scientists and research students.
List of Contributors
Alternative Anti-Infective / Anti-Inflammatory Therapeutic Options for Fighting Alzheimer’s Disease
Magda N. Tsolaki1,Euphrosyni S. Koutsouraki2,Georgios K. Katsipis3,Pavlos Gr. Myserlis1,Marilia A. Chatzithoma1,Anastasia A. Pantazaki3,*Abstract
Neurodegenerative diseases (NDs) have a serious impact on global health with no effective treatments yet available. Alzheimer's disease (AD) is an incurable, progressive neurodegenerative disorder, considered to be the most common cause of dementia. There is increasing evidence for the infectious/inflammatory etiology of AD. Although brain is assumed to be an immunologically isolated organ, many bacteria (Helicobacter pylori), viruses (Herpes simplex virus, influenza, CMV etc.), fungi, toxoplasma, are associated with AD. The presence of immune-related antigens around amyloid plaques, activated complement factors, cytokines and a wide range of related receptors in the brain of AD patients, led to the concept of “neuro-inflammation”. Persistent or acute neuronal and peripheral inflammatory response to infectious agents is gradually gaining more attention, as a risk factor for someone to develop sporadic AD. The human microbiome (HM) has a pivotal role in nutrition, health and disease. About 100 trillion bacteria from up to 1000 bacterial species inhabit the gastrointestinal (GI) tract, contributing, at least in part, to what is known as the “human-biochemical” or “genetic-individuality” and resistance to disease. Several pathologies, including AD and inflammatory bowel disease, are associated with alterations in gut microbiome. Microbes of the gut microbiota or of extracorporeal origin possess the ability of producing functional amyloid proteins. These amyloids, via lymphatic and systemic transport to the Central Nervous System (CNS), seem to have an important role in the expression of neurologic and psychiatric disorders, such as schizophrenia, anxiety and AD. Cross-seeding of the neurodegenerative disorder proteins may be induced by these amyloids. Moreover, chronic inflammatory response to these immune-reactive proteins can also be an important risk factor for CNS well-being. Therapeutic/preventive options for halting CNS disorders’ onset, could include: (a) Anti-inflammatory, anti-amyloid drugs (β-sheet breakers and other inhibitors of amyloid fibrillization), monoclonal antibodies, nanoparticles, which target pathological components of AD, or other medical interventions to remove infectious agents or to ameliorate their biochemical influence on GI-CNS tract, (b) Prebiotics to enhance the growth of desired organisms and reduce oxidative stress - a cause that has been implicated with AD, (c) Probiotics to provide both the desired bacteria, which increase the competitive effects with pathogens, and essential metabolic products, and to modulate the host immune system to resist in infection (d) The consumption of natural products, and the dedication to the Mediterranean (MeDi) and Asian (AsDi) Diets, abundant in bioactive compounds, are capable to prevent AD or reduce danger of AD, and strengthen the host's ability to confront infections. The significance of diet diversity leading to the microbiota diversity is a new clinically important concept. Finally, and (e) preventive medical and/or other therapies to alter the amyloids produced by bacteria, to decrease their production or stimulate their removal. This chapter is addressed to, and urges the excellent cooperation between experts of neurology/psychiatry, microbiology, biochemistry, dietary and nutritional sciences, in order to confront AD.
1. ALZHEIMER’S DISEASE (AD)
1.1. Epidemiology
AD is a progressive neurodegenerative disorder affecting millions of people worldwide.
Due to an increasingly aging population, AD represents a crucial issue for the healthcare system because of its widespread prevalence and the burden of its care needs. It is one of the most devastating diseases for the older population, and has become a major healthcare burden in the increasingly aging society worldwide. Currently, there are still only symptomatic treatments available, just to manage the symptoms and slow down disease progression. It is a progressive brain disorder that minimizes memory ability and other cognitive functions associated with intellectual and social skills. It has become a colossal medical and socio-economic challenge in the growing elderly population. As the most common dementia known, AD affects 5.4 million Americans, 10 million Europeans and nearly 47 million people worldwide [1]. The number of dementia cases is anticipated to triple by 2050 [2]. Two forms of AD are known: sporadic and familial AD. Sporadic AD affects people mostly after age 60 and makes up about 97% of all cases. Familial AD occurs at an earlier age between 30-50 and results when one parent passes a mutated gene associated with this dementia to their offspring. Each child of an individual with familial AD has a 50% chance of inheriting the mutated gene and developing this dementia. There is an amyloid precursor protein (APP) mutation [alanine-673-->valine-673 (A673V)] that causes disease only in the homozygous state, whereas heterozygous carriers were unaffected, consistent with a recessive Mendelian trait of inheritance. The A673V mutation affected APP processing, resulting in enhanced beta-amyloid (Aβ) production and formation of amyloid fibrils in vitro [3].
It is a considerable and galloping public health anxiety, with significant aug-mentation reflected in the future, especially in low-to-middle income countries [4]. Moreover, there is at present unanimity that a considerable analogy of cases are potentially preventable [5]. Preventing or delaying the clinical onset of dementia would have a substantial effect on disease numbers [6]. It has been suggested that approximately a third of AD cases could be attributed to seven potentially modifiable risk factors: diabetes, midlife hypertension, obesity, smoking, depression, cognitive inactivity, and low educational attainment [7].
1.2. Pathogenesis
Several hypotheses have been proposed for the pathogenesis of AD, but none of them is satisfactory enough to elucidate its full spectrum. Most possibly this is why the current therapeutic strategies have shown limited – if any – effectiveness [8]. In the last two decades, more evidence has supported a role for neuro-inflammation and immune system dys-regulation in AD [9-11]. It remains unclear whether astrocytes, microglia and immune cells influence disease onset, progression or both. Aβ peptides that aggregate extra-cellularly in the typical neuritic plaques generate a constant inflammatory environment. This engenders a protracted activation of microglial and astroglial cells that excite neuronal injury and provoke the alteration of the blood brain barrier (BBB), damaging the permeability of blood vessels. Recent data support the role of the BBB as a link between neuro-inflammation, the immune system and AD [12-14]. Hence, a thorough investigation of the neuro-inflammatory and immune system routes that affect neurodegeneration and unusual enthralling findings like microglia-originated micro-vesicles, particulate as inflammasomes and signalosomes will ultimately contribute to the elucidation of the pathological process. Finally, we should advance with attention in order to define whether the role of neuro-inflammation in AD is “causal or sequential”, but rather focalize on the identification of its precise pathological participation [15].
Two basic discoveries spurred research into inflammation as a driving force in the pathogenesis of AD. The first was the identification of activated microglia in association with the lesions [16]. The second was the discovery that patients with rheumatoid arthritis, who regularly consume anti-inflammatory agents, were relatively spared from the disease [17]. These findings led to the inflammatory pathways that were involved in AD pathogenesis. A pivotal advance was the discovery that Aβ activated the complement system [18]. This drew attention on the anti-inflammatory blockage of complement activation. More than 15 epidemiological studies indicated a sparing effect of non-steroidal anti-inflammatory drugs (NSAIDs) in AD; the longer the NSAIDs were used prior to clinical diagnosis, the greater the sparing effect. However clinical trials with NSAIDS in elderly people demonstrated many side effects [19].
It is accepted that the onset of AD initiates at least ten years before cognitive impairment allows clinical diagnosis, expunging the participation of NSAIDs, other anti-inflammatory drugs, or complement activation blockers, in the treatment of AD. The essential role of neuro-inflammation in AD has been indicated more than 30 years before. The inhibition of neuro-inflammation has become a key issue for AD and other chronic neurological disorders. Add-itionally, inflammation, as a reaction to amyloid deposition, is thought to accelerate cognitive decline [20].
The discovery that certain early-start familial forms of AD seems to be originated by an increased precipitation of Aβ peptides directs towards the hypothesis that amyloidogenic Aβ is closely associated in the AD pathogenic process [21]. There is proof that the primordial pathology in AD is stimulated by oligomeric species and Aβ-sheet comprising amyloid fibrils, originating from full-length Aβ1-42 [22]. Numerous variants of Aβ1-42 oligomers have been discussed as pathological factors in AD [23]. Recently, it was pointed out that, due to their biophysical characteristics, Aβ1-42 oligomers tend to aggregate into inert amyloid plaques in contrast to N-truncated Aβ4-42 and pyroglutamate Aβ3-42 (Aβ pE3-42)-m-peptides, who remain soluble and maintain their toxic profile for a longer time period [24, 25]. Although Aβ 4-42 is highly abundant in AD brains and was discovered as the first N-truncated peptide [26], it’s possible role in AD pathology has been largely overlooked [9].
1.3. Diagnosis
Current studies address four main questions:
Are the current diagnostic criteria for dementia reliable?Are the current diagnostic criteria able to establish a diagnosis for the widespread dementias in the aged people?Do laboratory trials ameliorate the precision of the clinical diagnosis of dementia?What co-morbidities should be evaluated in elderly patients undergoing an initial assessment for dementia?Diagnostic criteria for dementia have improved since 1994, using more accurate clinical definitions and the new techniques of neuro-imaging, biomarkers, and genetic tests [27].
1.3.1. Monoclonal Antibodies in the Diagnosis of AD
Current diagnostic methods using sequence-specific antibodies against less toxic fibrillary and monomeric Aβ42 run the risk of false positive. Hence, conformation-specific antibodies against neurotoxic Aβ42 oligomers have garnered much attention for developing more accurate diagnostics. Antibody 24B3, highly specific for the toxic Aβ42 conformer that has a turn at Glu22 and Asp23, recognizes a putative Aβ42 dimer, which forms stable and neurotoxic oligomers more potently than the monomer. 24B3 significantly rescues Aβ42-induced neurotoxicity, whereas sequence-specific antibodies such as 4G8 and 82E1, which recognize the N-terminus, do not. The ratio of toxic to total Aβ42 in the cerebral spinal fluid (CSF) of AD patients is significantly higher than in control subjects as measured by sandwich ELISA using antibodies 24B3 and 82E1. Thus, 24B3 may be useful for AD diagnosis and therapy [25].
According to the recent 2011 guidelines of the National Institute on Aging and the Alzheimer’s Association workgroup, CSF neurodegenerative biomarkers are now recommended in addition to patient’s medical history, clinical examination, neuropsychological testing and laboratory assessment in order to enhance the certainty of the diagnosis of AD in vivo [28].
1.4. Treatment
The current treatment of AD is based on four acetylcholinesterase inhibitors (AChEI) – Tacrine and its successors Donepezil, Galantamine, Rivastigmine – affecting the cholinergic system and memantine – an N-methyl-D-aspartate receptor (NMDAR) antagonist, affecting the glutamatergic system (Table 1).
Since 2003, no new drugs have been approved for treatment of AD. Despite recent debate regarding the so-called Aβ cascade hypothesis, new evidence supports the concept that an imbalance between production and clearance of Aβ42 and related Aβ peptides is a very early, often initiating event in AD. Confirmation that presenilin is the catalytic site of γ-secretase has provided a linchpin: all dominant mutations causing early-onset AD occur either in the substrate APP or the protease (presenilin) of the reaction that generates Aβ. Duplication of the wild-type APP gene in Down's syndrome leads to Aβ deposits in the teens, followed by microgliosis, astrocytosis, and neurofibrillary tangles typical of AD [29]. Apolipoprotein E ε4, which predisposes to AD in > 40% of cases, has been found to impair Aβ clearance from the brain [30]. Soluble oligomers of Aβ42 isolated from AD patients’, can decrease synapse number, inhibit long-term potentiation, and enhance long-term synaptic depression in rodent hippocampus. Moreover, a cerebral injection of these isolated peptides in healthy rats, impair memory [31]. The human oligomers also induce hyper-phosphorylation of tau at AD-relevant epitopes and cause neuritic dystrophy in cultured neurons [32]. Crossing human APP with human tau transgenic mice enhances tau-positive neurotoxicity. In humans, new studies show that low CSF Aβ42 and amyloid-PET positivity precede other AD manifestations by many years. Most importantly, recent trials of three different Aβ antibodies (solanezumab, crenezumab, and aducanumab) have suggested a slowing of cognitive decline in post hoc analyses of mild AD subjects [33]. Although many factors contribute to AD pathogenesis, Aβ dys-homeostasis has emerged as the most extensively validated and compelling therapeutic target. To date, phase 3 immunotherapy trials with humanized monoclonal antibodies (mAb) targeting cerebral amyloid in patients with mild to moderate AD have not shown significant improvements in cognitive or functional outcomes [21, 34, 35]. Ongoing clinical trials with Aβ antibodies (solanezumab, gantenerumab, crenezumab) in early stages of the disease seem to be promising, while vaccines against the tau protein (AADvac1 and ACI-35) are now in early-stage trials [36].
2. INFECTION AND INFLAMMATORY RESPONSE
Inflammation is the process by which the immune system defends the host from organisms or material perceived as foreign and potentially threatening. As far back as the first century AD, the Roman encyclopaedist Celsius identified inflammation as a constellation of four physical signs: Heat, pain, redness, and swelling, or in classical medical language, “Calor, dolour, rubor, and tumour.” They reflect the actions of various cellular and chemical mediators that are part of the immune response [37]. Affected individuals frequently carry tell-tale signs of inflammation in their blood or in the organ system involved. These tell-tale signs, referred to as biomarkers or inflammatory markers, are found in all people, but are frequently at higher levels in people with chronic inflammatory diseases. The inflammatory markers include substances such as C-reactive protein, tumour necrosis factor (TNF), prostaglandin E2 (PGE2), and others. Inflammatory markers are signs of immune system activation, a process emerging as central to the aetiology of chronic diseases in the developed world.
It has become clear that inflammation contributes to chronic neuro-degeneration but its precise role is not clear yet and there are no effective treatments for slowing the progression of chronic conditions such as AD and Parkinson’s Disease (PD). There is substantial epidemiological evidence that inflammatory co-morbidities are significant risk factors for dementia [38-40] and taking non-steroidal anti-inflammatory drugs protects against subsequent development of AD [41].
Consistent with a role of co-morbid inflammation, many researchers have shown that systemic inflammation can robustly alter brain inflammatory status, inducing a switching of microglial phenotype from ‘primed’ to activated, with the consequence of acutely elevated brain levels of IL-1b [42-44]. The pro-inflammatory cytokine IL-1b has been shown to contribute to impaired cognitive function and decreased neuronal viability [45-47]. In animal models of chronic neurodegeneration, such superimposed inflammatory activation can exacerbate the progression of neurodegenerative disease [48-50]. However, the mechanisms by which systemic inflammation exacerbate neurodegeneration remains unclear.
Another very interesting phenomenon is the aging of the immune system which is a continuous and dynamic process and it may be secondary to mechanisms activated by the response to the pathogens.
Innate immune response is partially affected by human aging. A decrease in the main functions of innate immunity cells, as a consequence of changes in the expression of a variety of innate immune cell receptors and altered signal transduction pathways have been reported. These defects may result in a reduced capacity to respond against bacterial and viral pathogens [51].
Adaptive immune responses also progressively decline with age [52]. Recent investigations focused on immune senescence suggested that the progressive decline of immune defense efficiency might be an adaptation mechanism to the microorganism exposure experienced by the aging organism over the life time [53-56]. Therefore, chronic sub-clinical infections represent important env-ironmental factors, able to induce a reshaping of the immune system by antigen load during aging.
Several pathogens are able to induce a reshaping of adaptive immune responses and to impair the regulation of both peripheral and central immune defensive mechanisms. Defective immune defenses against some pathogens, both viruses and bacteria, may play a role in triggering chronic inflammatory responses and directly or indirectly activate neuro-inflammation [57]. In the individuals developing clinical AD, immune protective mechanisms appear to be defective. Therefore, persistent subclinical infections activate and amplify chronic neuro-inflammation and neurodegenerative mechanisms leading to progressive neuronal loss and cognitive impairment.
3. RELEVANCE OF INFECTION/ INFLAMMATION TO AD PATHOGENESIS
3.1. The Role of the Innate Immune System in AD Brain
Immune responses in the CNS can be mediated by resident microglial cells and astrocytes, which are immune cells residing in the CNS and lack direct counterparts in the periphery. Furthermore, CNS immune reactions often take place in virtual isolation from the innate/adaptive immune interplay that characterizes peripheral immunity. However, microglias and astrocytes also engage in significant cross-communication with T-cells that have access to the CNS and other components of the innate immune system. It is known that chronic neuro-inflammation includes not only the long-term activation of microglial cells (and the resulting prolonged release of inflammatory facilitators), but also the resulting peak in oxidative stress. This pronounced release of inflammatory facilitator results in triggering the persistent inflammatory cascade, by recruiting additional microglial cells, effecting their proliferation, and resulting in the increased release of inflammatory factors. NDs, including AD, have been associated with chronic neuro-inflammation and elevated levels of a number of cytokines.
3.2. Inflammation in the Brain
Inflammation in the brain is largely regulated by the support cells of the CNS, the glial cells. This group of cells includes the astrocytes (which assist the metabolism in the neurons), the oligodendrocytes (which secrete the myelin insulating the neuronal axis and, thus, securing the efficient propagation of the nerve impulses) and the microglias (which serve as a local specialized immune system). Activation of the glial cells is a pivotal aspect of brain inflammation. When activated, microglias produce inflammatory facilitators, which activate other cells inducing the production of additional inflammatory facilitators. Thus, these molecules are able to complete positive feedback loops, thereby amplifying the resulting inflammation. Inflammation of the brain becomes more frequent with senescence and the process has been found to include the increased activation of microglia and astrocytes. Brain inflammation is also a key feature of AD. Even from the early stages of this ND, both oxidative damage and inflammation are usually present, and they are understood to be the result of amyloid plaques formation and the widespread apoptosis of nerve cells [58, 59].
It has been suggested that in AD, there is a period of equilibrium before the clinical outbreak of the disease; this equilibrium involves a competition between the restorative function of the immune system and the factors precipitating the disease. The symptomatic aspect of the disease is only revealed, when the immune system fails to cope with such locally-emerging threats [60]. This failure of the immune system could be the result of increasing levels of disease-causing factors, and that the immune system is no longer able to contain them, or a situation in which the immune function deteriorates or is suppressed, while the disease progresses, because of factors related (directly or indirectly) to the underlying cause of the disease. T-cell deficiency can be manifested at several levels: deficiency in memory T-cells specific for certain antigens, increased levels of regulatory T cells or of myeloid suppressor cells (MSCs) that suppress effectors’ T-cell activity, or premature aging of the adaptive immune system [61].
Until recently a separating specialization was in place, with mostly neuroscientists studying the brain and mostly immunologists studying the immune system, and this specialized approach generated the tendency to consider these two systems as isolated entities. However, since more data has accumulated, strongly suggesting the importance of the immune system in regulating the aging processes in the brain, it became evident that these systems can no longer be considered in-dependent and separate, and the need for a new interdisciplinary approach has solidified. A cardinal question that needs to be addressed is whether, with age, certain immune and inflammatory pathways become excessively activated and this, in turn, promotes degeneration, or if weak immune responses, which fail to cope with age-related stress, may contribute to disease [62].
3.3. Neuro-Inflammation in AD
There are many parallels between different NDs including atypical protein assemblies as well as induced cell death. Neurodegeneration can be found in many different levels of neuronal circuitry ranging from the molecular to systemic [63, 64]. Once viewed as a region where the immune system acts with restrictive access, because of the presence of the BBB, it is now clear that while the peripheral immune access is, indeed, restricted from and heavily regulated in the CNS, the last retains the ability to offer dynamic immune and inflammatory responses to a variety of attacks [65]. Infections, toxins, trauma, stroke and other hostile factors are capable of triggering an immediate yet transient activation of the innate immune system within the CNS [66, 67]. This acute neuro-inflammatory response includes the activation of the resident immune cells (microglia), which mature into phagocytes and the release of inflammatory mediators, such as cytokines and chemokines [68].
The sustained release of inflammatory mediators works to perpetuate the inflammatory cycle, activating additional microglia, promoting their proliferation, and resulting in further release of inflammatory factors. Due to the chronic and persistent nature of the inflammation, there is an often compromise of the BBB which increases the possibility of infiltration by peripheral macrophages into the brain parenchyma that result in further perpetuating the inflammation [65]. Under such condition, rather than assuming a protective role (as acute neuro-inflammation does), chronic neuro-inflammation has been shown to often have a detrimental and damaging effect on nervous tissue. Thus, whether neuro-inflammation results in either beneficial or harmful outcomes, in the brain may well depend on the very duration of the inflammatory response.
AD is associated with chronic neuro-inflammation as well as elevated levels of several cytokines [69-71]. Neuro-pathological and neuro-radiological studies have pointed towards these neuro-inflammatory responses, to initiate prior to any significant loss of neuronal populations in the progression of AD. While there is no clear evidence to support a pivotal role to any particular cytokine in the direct triggering of AD, cytokine-driven neuro-inflammation and neurotoxicity may well act as modifiers during the progression of the disease. Nevertheless, inflammatory challenges might act as triggers to uncover underlying genetic tendencies that contribute to neuronal dysfunction and death. Alternatively, viruses or bacteria might “prime” the immune system to respond aberrantly to subsequent environmental challenges. If the available evidence supports a role for neuro-inflammation in AD, it may be possible to alter the progression of disease, in affected individuals, with anti-inflammatory therapy [72].
3.4. The Role of Microglias
In the CNS, the resident tissue macrophages system consists of microglias, which are the principle mediators of inflammation. In their resting state, microglias have been observed that form a small cell soma and numerous branching processes (a ramified morphology). In healthy brain tissue, these processes are dynamic structures that are extended and retracted depending on the immediate microenvironment. During the resting state, several “key” surface receptors are expressed at low levels; these include the tyrosine phosphatase (CD 45 - also known as the leukocyte common antigen), CD14, and CD11b/CD18 (Mac-1). Moreover, cell surface receptor-ligand pairs, such as CD200R/CD200, are present to maintain neuron-glias’ communication in the CNS [73].
In the presence of an activating stimulus, microglial cell-surface receptor expression is modified and the cells change from a monitoring role to protecting and repairing ones [74]. In addition to the up-regulation of the “key” surface receptors mentioned above, there is also up-regulation of proteins such as CD1, lymphocyte function-associated antigen 1 (LFA-1), intercellular adhesion molecule 1 (ICAM-1 or CD54), and of the vascular cell adhesion molecule (VCAM-1 or CD106). Activated microglias secrete a variety of inflammatory mediators including cytokines (TNF, and interleukins IL-1β and IL-6) and chemokines (macrophage inflammatory protein MIP-1α, monocyte chemo-attractant protein MCP-1 and interferon (IFN) inducible protein IP-10) that promote the inflammatory state. The morphology of the cells alters from ramified to amoeboid, as they assume their phagocytic role. These moderately active microglias are thought that perform beneficial functions, such as scavenging for neurotoxins, removing dying cells and cellular debris, and secreting trophic factors that promote neuronal survival. Persistent activation of brain-resident microglias may decrease the effectiveness of the BBB and promote quickened infiltration by peripheral macrophages, the phenotype of which is critically determined, by the microenvironment they encounter in the CNS [18].
Hypoxia and trauma reduce neuronal survival and, indirectly, trigger neuro-inflammation, as microglia becomes activated in response to the attack, in an attempt to limit further injury. Infectious agents activate microglias either through damage to infected cells or direct recognition of foreign (viral or bacterial) proteins. Following exposure to neurotoxins, such as the mitochondrial complex I inhibitor 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), the dopamine analogue 6-hydroxydopamine (6-OHDA), or the pesticide paraquat, microglias become activated and primed. Microglial responses to these toxins may contribute to neuronal dysfunction and eventually quicken neuro-degeneration [54]. In addition, genetic mutations that give rise to increased production of toxic oligomeric, aggregated/truncated, or oxidized protein species, promote sustained activation of microglias, and may prime the immune system for abnormal responses to subsequent attacks. Regardless of the initiating factor, all of these external or internal stimuli seem to retain the ability to precipitate a self-perpetuating inflammatory response, which, if is allowed to continue unhindered, may contributes to neuronal death.
3.5. Oxidative Stress in the Brain
Oxidative stress and inflammation are among several mechanisms, which interact through a number of pathways that contribute to neuronal loss. Other mechanisms include excessive stimulation of neurons (excitotoxicity), mis-folding and dysfunction of cardinal proteins, deregulation of gene expression, mitochondrial dysfunction, problematic calcium homeostasis, altered phosphorylation, cytoskeletal disorganization, increased extracellular matrix turnover, altered proteases/inhibitors, cell membrane malfunctions, reduced blood supply, and ineffective stress responses. These processes seem to be interconnected. Within the mitochondria, ROS are continuously produced by oxidases and the electron transport chain associated with oxidative phosphorylation. Other reactions pr-oducing ROS include the activities of cyclooxygenases, lipoxygenases, dehydrogenases and peroxidases. The subcellular sites, where these reactions take place include virtually all components of the cell, including the nucleus, the mitochondria, the lysosomes, the peroxisomes, the endoplasmic reticulum, the cytoplasm and the plasma membrane.
Oxidative damage to mitochondria has also been proposed to be a very important underlying finding in AD. This theory is supported by the observed reduction in brain metabolism, which occurs in AD patients, indicating reduced mitochondrial function. Reduced brain metabolism has been reported to precede the development of abnormalities in neuropsychological testing; suggesting that impeded brain metabolism plays a crucial role in the web of AD pathogenesis [55]. These findings are part of a growing body of evidence, suggesting that oxidative stress is indeed an important pathologic mechanism in NDs, and its onset can begin early in the diseases’ process [56-60].
3.6. Oxidative Stress and Inflammation
Oxidative stress and inflammation may follow distinct biochemical cascades; nevertheless, both processes are closely interweaved and generally function in tandem, particularly in the brain, which is especially prone to oxidative stress. Whenever evidence of oxidative stress is found in brain specimens (i.e. ROS and the markers of their damage), evidence of inflammation (cytokines and other inflammatory mediators, activated immune cells, etc.) is also generally present. While much remains to be explored regarding oxidative stress and inflammation - and their interactions - at least two major points of convergence have been recognized and these explain their tendency to occur simultaneously and positively reinforce each other. The inflammatory response can trigger or increase oxidative stress and then the resulting activated microglias produce ROS, in their quiver of defences against pathogens and their markers. If the ROS overwhelm the cell’s detoxification capacity, oxidative stress results in consequent damage to essential molecules and tissues [59].
Oxidative stress can trigger or increase inflammation through the activation of nuclear factor kappa B (NF-κB), which is known to be sensitive to oxidative stress. NF-κB is a transcription factor and, as such, it controls the expression of various genomic targets, including a variety of genes involved in the inflammatory response. NF-κB is generally associated with chronic inflammation and has also been linked to several forms of cancer with evidence suggesting that NF-κB is pivotal in the pervasive effects of oxidative stress [75].
At the same time, evidence is suggestive of Aβ, an important factor in AD, interacting in numerous ways with inflammation and oxidative stress. While there is evidence of complex interactions - with Aβ causing ROS/inflammation [76], and ROS/inflammation causing Aβ production [77, 78], an increasing body of evidence point towards this process to be initiated commonly by oxidative stress and inflammation [79-82].
3.7. Toll-like Receptors as Major Players in Neurodegeneration
Toll-like receptors (TLRs) are the main trans-membrane protein receptors on innate immunity cells; they bind typical, highly conserved structural motifs essential for pathogen survival, as lipopolysaccharides (LPSs) of gram-negative bacteria, peptide-glycans and lipo-peptides of gram-positive bacteria, fungal zymosan, viral double-stranded and single-stranded RNA [83, 84]. Nearly all cells within the human body express TLRs, including cells within brain tissue; both neurons, and glial cells. In cell injury and infection TLRs trigger innate immune response and modify adaptive immune response [85] and also participate in several non-immune processes: are engaged in brain development, neurogenesis, and release neurotrophic, neuro-protective factors [84].
TLRs could be activated not only by invading pathogens, but also by various mediators released from stressed or injured cells, in the absence of microbial infection [83]. In aging human brain, up-regulated transcription of pro-inflammatory cytokine genes is accompanied by markedly changed transcription of TLR receptor proteins; expression of TLR1, TLR2, TLR4, TLR5 TLR7 is elevated, whereas that of TLR9 is down-regulated. The cellular source of over-expressed TLRs in aging human brains was identified to be the mononuclear phagocytes – microglia [86]. Altered expression of TLRs in normal aging brain could be associated with greater susceptibility to AD in aged people.
3.8. TLRs in AD
Aβ is able to activate TLRs and, hence, elicits the production of pro-inflammatory cytokines, reactive oxygen and nitrogen radicals in activated microglial cells [87, 88]. The recognition of fibrillary Aβ by microglial cells occurs through its interaction with a cell surface receptor complex for fibrillary proteins, including CD36, CD47, integrin α6β1, and scavenger receptor A [89]; however, activation of TLR2, TLR4 and their co-receptor CD14 is required for linking the recognition event to mechanisms of Aβ phagocytosis and reactive oxygen production by microglia [88].
Recently, it has been demonstrated that TLR4, which is mainly expressed on microglias within the brain tissue, can mediate extensive neuronal and oligodendrocyte death, when activated with LPSs in mixed cell cultures and in vivo in mice. In primary cultures of mouse parietal cortex neurons Aβ42 and lipid peroxidation product 4-hydroxynonenal (HNE) increased expression of TLR4 which lead to neuronal apoptosis, whereas neurons from TLR4 mutant mice were protected against apoptosis induced by Aβ42 and HNE [90]. The loss of function mutation of tlr4 gene strongly inhibits microglial activation by fibrillary Aβ, resulting in significantly lower release of IL-6, TNF-α and nitric oxide [76].
These results strongly suggest an important role played by TLR4 in neuro-inflammation and neurotoxicity in AD [76]. Humans bearing functional tlr4 gene polymorphism (Asp299Gly) exhibited reduced inflammatory reactions and lower susceptibility to late-onset AD [91]. It should be emphasized, that an activation of microglial TLRs in early stage of AD elicits desired effect by reducing the Aβ burden; however, in more advanced stages of the disease, TLRs activation encourages neuro-inflammation and participates in neurodegeneration. Therefore, any potential treatment approach directed on TLRs should be modified to reflect the corresponding stage of the disease.
3.9. Conclusions
A growing body of research findings highlights the role of “immune molecules” (such as the microglias, the complement, the class-I major histo-compatibility complex and the TLR system of innate immunity) in CNS development and plasticity as well as in the general pathogenesis mechanism of neurodegeneration [83, 84, 92, 93].
Even in the absence of clear evidence to attribute a clear role for the classical inflammatory cytokines (such as TNF-α and IL-6) in neurodegeneration, and a gain of neurotoxic function by microglias, albeit, there are also promising experimental results, which describe deficits of immune activation in deg-enerating brain tissue, that leave room for loss-of-function paradigms. Apart from vaccines, however, medicine appears to be more successful in inhibiting the immune system rather than stimulating it. A strategy for blunting inflammatory reactions within the brain tissue should be focused on TLRs on microglias or macrophages during clinical course of neuro-degeneration. In the meantime, we need to further explore and understand the molecular events in immune cell function that occur in healthy people [63, 72].
4. INFECTIVE CAUSES
Many authors speculate that mental illnesses could be epidemic [94, 95]. Although the aetiology of the many neuropsychiatric diseases remains elusive, it is thought to entail genetic and environmental causes, and microbial pathogens have also been envisioned as contributors to the phenotype. The inability to establish unique and consistent relationships between specific environmental factors and individual neuropsychiatric conditions, has recently led to reflection upon host responses to these agents. These conditions have been attributed to various imbalances triggered either by infection, xenobiotics, diet and other environmental agents [96]. Recently, the vigorous search for microbes, their metabolites and other indications of a common mechanism, which leads to a neuropsychiatric illness, involves also the auto-immunity.
This opinion was empowered, as evidence accumulated, to support the theory that errors, in the bidirectional communication between the brain and the immune system, are substantial contributors to the aetiopathology of a big spectrum of conditions [97, 98]. New evidence supports the possibility that, except the microbes associated with infections, bacteria of the gut microbiome, also known as microbiota, can produce auto-antibodies, which target the brain, and they could provide the critical correlation between neuropsychiatric disorders and infection.
Trillions of microorganisms, collectively designated as the gut microbiota, reside throughout the GI tract, broadening host metabolic [99], digestive [100], immune [101], and neural function [102
