Inflammation Studies

Alzheimer disease (AD) is the most common cause of dementia in the elderly, accounting for 65–70% of all cases (Jellinger, Janetzky, Attems, & Kienzl, 2008). The other dementias are of the Parkinson 's group, the fronto-temporal group and the vascular group. The total worldwide yearly costs for the treatment and care of patients suffering from dementia are estimated to be around 250 billion US dollars. The lifetime risk for AD between the ages of 65 and 100 is 33% for men and 45% for women with an annual increase of 1–2% in the seventh decade to almost 60% in the 10th decade with doubling every 5 years (Jellinger et al., 2008). AD is incurable, and thus represents a major public health problem. AD represents a challenge to humanity due to its relatively recent discovery, progressive nature of the illness, and complex diagnosis.

Alzheimer’s disease (AD) is a progressive and fatal form of dementia, frequently seen in the elderly altering their cognition, thought process and behavior. AD is reported in about half of patients that have a dementia diagnosis; one study states that about 10.3% of the population over 65 years is affected by dementia with an increase to almost 50% over the age of 8 (Beattie, 2002). Alzheimer’s disease is not a normal part of the aging process in humans, but rather found in a group of diseases that affect the brain leading to a decline in mental and physical control. AD when diagnosed has a very slow and gradual course, initially affecting the individual’s short term memory (Beattie, 2002). Alzheimer’s disease is the 6th leading cause of death, affecting more than five million people in the United States and is also one of the most common forms of dementia. Dementia can be defined as a disorder of progressive cognitive impairment severe enough to affect daily functions of an individual’s life (Fillit, et al., 2002).

Alzheimer’s disease, also referred to as AD, is a form of dementia that affects millions of people worldwide. AD is best known for causing memory loss in those who suffer from it, as well as affecting decision-making, language, and decision making progressively over time (Zou et at, 2014). According to Zou et el (2014), the symptoms of AD are caused by a build of plaques in the neurons of the brain. Alois Alzheimer discovered the disease, which was later named after him, when a woman at the age of 51 presented to him with a case of dementia that was new to him. Alzheimer was able to deduce the behavior of the woman with certain cognitive features, as well as through autopsy proceedings, that the symptoms were caused by “senile plaques” within

It is a disease that we haven’t cured yet but instead have only come up and still coming up with treatment strategies to alleviate its symptoms. AD was first described in 1906 by a German psychiatrist by the name of Alois Alzheimer whilst he was performing a histophathologic study of his patient’s brain, a patient who had been suffering from dementia. His patient’s brain’s autopsy brought to light the presence of two types of lesions, which are senile plaques and neurofibrillary tangles. He saw a visible difference in the brain tissue for it was severely damaged by these lesions. Since then, our knowledge of AD’s cellular and molecular alterations has increased and we have come up with various hypotheses for AD that may soon help in developing effective preventative and therapeutic strategies. One of the most prevailing hypotheses that have already leaded to a number of therapeutic approaches is the amyloid cascade hypothesis. Hence, the following essay will explore the pathology of the amyloid cascade hypothesis and the evidence for and against it. It will also touch upon current progress in clinical trials that test the

Dementia is a syndrome which is progressive in nature, characterized by impairment of memory and loss of intellectual ability.1 Decreased level of Acetylcholine in the brain, neuro-inflammatory reaction, rise in the oxidative stress and hypercholesterolemia have been reported to play an important etiological role in the memory decline.2 Alzheimer’s Disease (AD) is the most common form of dementia which is a progressive and a neurodegenerative disease characterized by the presence of senile plaques rich in insoluble aggregates of β amyloid and neurofibrillary tangles in the brain. AD has been estimated to account for 50–60% of dementia cases in persons over 65 years of age worldwide.3 Alzheimer’s Disease International

Instead of being recognized and attacked by T cells, bacteria are recognized and attacked by complement proteins. “Complement proteins assist in bacterial killing via three pathways, the classical complement pathway, the alternative complement pathway or the lectin pathway. The first steps of the classical complement pathway require the binding of antibodies to the surface of the target bacterium” (Immune, 2016). At this point, the antibodies are handled by protein complexes which bind to the surface of the invader (much the same as the process of T cells in viruses). In other words, the body goes through a similar reaction of identifying and then attempting to destroy the invader, including the formation of a membrane attack complex. “MAC can insert into the cell membrane of Gram-negative, but not Gram-positive, bacteria. There, it produces pores that allow the entry of membrane damaging molecules, such as lysozyme, and makes the bacterium susceptible to osmotic lysis” (Immune,

The immune systems helps the body fight off the other parts of our bodies and harmful substances such as disease, infection or bacteria. Some strategies for ensuring a healthy immune system are: don’t smoke, move your body which mean exercise regularly, eat diet food such as fruit and vegetable, get a good night sleep and maintain your healthy weight. These strategies are a good way to start giving your immune system the upper hand.

To understand how microbes may be involved in AD, we first must look at what physically happens to the brain with this disease. There are two distinct aspects involved in Alzheimer’s disease; beta-amyloid plaques and tau tangles. Beta-amyloid plaques are formed when the amyloid precursor protein (APP) which is present in the membrane of neurons (alz.org) is cleaved off by beta and gamma-secretases (Chen et al., 2001). In a normal brain, alpha-secretase does the cleaving and the body processes APP on its own (Chen, et al., 2001). In AD, the small pieces join to form beta-amyloid plaques but as smaller individual pieces they can interfere with nerve signaling

Amyloid β-peptide (Aβ) is the major component of the senile plaques, and the amount of Aβ to form the plaques is correlative with the degree of neuronal damage and cognitive deficit. Although four million new cases of dementia are recognized yearly, and nearly 70% of these cases are ascribed to AD, there is still now not fully elucidated and no efficient method for its

Aim 1 Expected Results. It is expected that Alzheimer’s patients with MDD will have higher levels of IL-6 and TNF-α than those without MDD; there will not be a significant difference in IL-1β and IFN-γ levels between the two groups. It has been demonstrated that major depression patients have elevated levels of IL-6 and TNF-α12. Additionally, females and males will have similar levels of IL-1β and TNF-α levels. Females before menopause may have had lower levels of pro-inflammatory cytokines due to the presence of estradiol, the female sex hormone, but its level drops dramatically after menopause, neglecting its neuroprotective effects of down-regulating pro-inflammatory cytokines5. The null hypothesis

Dr. Colton’s claim that the immune system suppression causes Alzheimer’s rests upon the questionable assumption that the DFMO drug completely stops the disease from progressing further (Chapter 4). Although evidence points towards the immune system as the cause, the immune system in the mice might not be as sophisticated compared to a humans. This potentially means the microglia in humans might not consume arginine unlike mice (refutation).

The overproduction of microglial pro-inflammatory mediators is neurotoxic, which raises great concern that systemic inflammation exacerbates or possibly triggers neurological diseases [6]. It is known that inflammation has an essential role in the progression of Alzheimer’s disease (AD), since amyloid-β (Aβ), which are brain plaques that are formed during the disease, are able to activate microglia, initiating an inflammatory response, could have different consequences for overall neuronal survival. On one hand, microglia may delay the progression of AD by contributing to the clearance of Aβ, since they phagocytose Aβ by releasing enzymes responsible for Aβ degradation. Since it is known that Arginase, as a component of macrophage microglial cells, could be overproduced, leading to the catabolism of arginine. Thus, instead of protecting the brain, it is actually destroying

Co-existence of the gut microbiota and cells within mammalian hosts can then be understood on a molecular level, highlighting the significance of microbe-host interactions in studying health and disease (Hooper 2012). The main function programmed into host cells is to prevent entry from foreign invaders through the recognition of self from non-self. All bacterial cells are comprised of elements that can be detected by pattern recognition receptors (PRRs) on host cells. These ligands are pathogen-associated molecular patterns (PAMPs) such as nucleic acids, flagellin and lipopolysaccharides which are attached to bacterial membrane and can trigger inflammatory immune responses. Due to the relative abundance of these commensals, mechanisms of adaptation have been employed in order to induce a tolerance in host cells (Palm 2015). An additional component of the ability to tolerate microbes is mediated by antigen-presenting cells (APCs) of the immune system that are crucial to induce a response upon exposure to non-self. Macrophages are APCs that have a method of tolerance by suppressing the secretion of cytokines upon detecting commensals during a state of homeostasis. This mechanism will prevent the cascade of an inflammatory response to gut microbiota as they are identified as commensals rather

IgA antibodies play a major role in maintaining homeostasis at mucosal surfaces including the gastrointestinal tract (Brandtzaeg, 2013; Gutzeit et al., 2014). Peyer’s patches (PP) are critical inductive sites in the mammalian small intestine where naïve B cells are initially activated by exogenous luminal antigens and then differentiate with T cell help into IgA plasmablasts that circulate in the blood before preferentially homing to the intestinal lamina propria to become resident IgA-secreting plasma cells (Cebra et al., 1998; Macpherson et al., 2008). High local concentrations of TGF-β and retinoic acid and the presence of IL-21-producing follicular helper T (Tfh) cells are all factors that promote IgA class switching in PP (Cao et al., 2015; Cerutti, 2008). Many of the dimeric SIgA antibodies produced by lamina propria IgA-secreting plasma cells are transcytosed across the epithelial layer and bind to commensal enteric bacteria after reaching the lumen (Benckert et al., 2011). SIgA directed against bacterial antigens has a variety of effects that help to shape gut microbial populations including immune exclusion from the inner mucus layer, inhibition of bacterial motility, impairment of bacterial fitness and neutralization of toxins (Cullender et al., 2013; Gutzeit et al., 2014; Peterson et al., 2007). A high level of bound IgA on gut resident bacteria may flag those commensal bacteria with a propensity to elicit a strong host immune response and induce

Pro-inflammatory changes lead to significant impairment in cognitive function in mouse models of AD {Heneka, 2002 #28}, {Heneka, 2006 #30}, {Jardanhazi-Kurutz, 2010 #38}, {Kalinin, 2007 #39} {Pugh, 2007 #69}. In addition, DSP4-mediated destruction of NE-ergic cells leads to decreased migration and phagocytosis by microglia and reduced colocalization between microglia and Aβ {Heneka, 2010 #29}. This suggests that a loss of NE-ergic cells could result in lower microglial cell function and a decrease in Aβ clearance in patients with AD. Indeed, DSP-4 injections in the Ts65Dn mouse model of DS has resulted in increased hippocampal inflammation and accelerated degeneration into AD-like pathology {Lockrow, 2011 #54}.