Alzheimer's Disease Summary

AD is a progressive age-related neurodegenerative disorder that poses increasing challenges to the global healthcare system and economic development. AD is characterized by extracellular neurotic plaques composed of Aβ deposits and intracellular neurofibrillary tangles composed of hyperphosphorylated tau with progressive loss of synapses in the brain [1]. Evidence demonstrates a potential link between oxidative stress, mitochondrial dysfunction and AD development [2]. Oxidative damage has been known to occur at a very early stage of AD even prior to Aβ plaque formation and the onset of symptoms [3, 4, 5]. Several cellular changes by oxidative stresses have been related with Aβ plaques formation and pathophysiological events of AD [6].

The spontaneous self-aggregation of Aβ into multiple coexisting physical forms, including oligomers (two to six peptides), leads to their coalescence into intermediate assemblies. In addition to this, β-amyloid can also grow into fibrils, which arrange themselves into β-pleated sheets to form the insoluble fibers of advanced amyloid plaques. Soluble oligomers and intermediate amyloids are the most neurotoxic forms of Aβ. In brain-slice preparations, synapses are toxified by dimers and trimers of Aβ. However, the severity of the cognitive defect in Alzheimer’s disease is in correlation with the levels of oligomers in the brain, not the total burden of Aβ. Neuronal activation rapidly increases Aβ secretion at the synapse, a process tied to the normal release of vesicles containing

In spite of significant improvements in our knowledge of the pathogenesis of AD over recent decades, the precise mechanisms leading to AD development remain elusive. Over the years, several different hypotheses have been postulated to address the pathological lesions observed in AD. Indeed, oxidative stress has been consistently observed as an underlying biochemical anomaly in several neurodegenerative diseases including AD. However, whether oxidative stress presents a causal role or is secondary to AD pathogenesis remains unclear.[39] Markers for oxidative stress have been reported during early development of the disease and in patients with mild cognitive impairment well before the onset

Abstract: The link between protein aggregation and the free radical theory of aging remains unresolved, and this proposal aims to determine whether protein aggregates, such as amyloid-beta (Aβ), cause mitochondrial dysfunction and increase the production of reactive oxygen species (ROS). Furthermore, these aggregates may create local regions of increased microviscosity and hinder diffusion of essential nutrients and harmful cellular wastes. The reduced diffusion may be the reason for the hypothesized increased ROS production and/or may facilitate secondary cell death pathways. The amyloid field, mainly in relation

Alzheimer’s disease (AD) is a debilitating illness of the nervous system, affecting millions of geriatric population worldwide. Numerous factors are involved in the disease etiology viz. tau phosphorylation, amyloid β protein (Aβ) accumulation, lipid dysregulation, oxidative stress and inflammation. Among all factors oxidative stress plays a central role in the pathogenesis of AD leading to neuronal dysfunction and cell death (1). Oxidative stress is caused due to the increased production of reactive oxygen species (ROS) which denatures biomolecules such as proteins, lipids and nucleic acids through pathological redox reactions(2). Increased oxidative stress also results in excessive lipid peroxidation, weakening the cell membranes, causing

While issues regarding concentration levels of Aβ, the types of Aβ and the mechanisms of its production remain poorly understood, some information has been found. For instance, the continuous overproduction of Aβ at dendrites or axons acts locally to reduce the number and plasticity of synapses (Parihar, 2010). Moreover, in mouse models for AD, the area of amyloid plaques is characterized by highly dysmorphic neurites and spine turnover causing a net loss of spines (Parihar, 2010). Such abnormalities in dendritic spines were found to develope before appearance of clinical symptoms in AD--likely due to cognitive reserve (Parihar, 2010). These characteristics could be caused by Aβ oligomers, which block long term potential (LTP) and directly induce long term depression (LTD), spinal loss and memory loss(Parihar, 2010). Likewise, in hippocampal culture, the soluble Aβ produced

Ceruloplasmin is a serum ferroxidase that carries more than 90 % of copper in plasma and plays an important role in iron homeostasis as well as antioxidative functions [105]. Ceruloplasmin best known as copper binding protein, found in the plasma of vertebrate species, and is mainly synthesized by the liver [106]. After ceruloplasmin was originally isolated from plasma by Holmberg and Laurell [107], this protein quickly became the subject of many investigations concerning its function, molecular structure and the physical properties of the copper ions bound to it [106, 108-111]. The ceruloplasmin gene was identified on the human 3q25 chromosome with a molecular weight of ~132 kDa [112]. The molecule is composed of six compact domains, with large loop insertions, and is characterized by the presence of three types of spectroscopically distinct copper sites.

The life expectancy is now doubled from the last century in the developed countries due to the revolution progress in medicine and health mainly to chronic diseases. Alzheimer’s disease (AD) is one of the most well-known and familiar diseases in the modern societies AD was first reported by Alois Alzheimer in 1907.The AD is the most common type of dementia and a neurodegenerative disease characterized by the damage of nerve cells in the cerebral cortex. The health statistics report that AD disease affects more than 50 million people worldwide in 2003, it is expected this number to increase to 114 million by 2050.(1) It is reported that AD disease affect one in three people over the age 85.(2) The symptoms of AD include depression, apathy, anxiety, agitation, aggression, delusions, hallucinations, wandering, and inappropriate sexual behaviours.(3) AD patients suffer from decrease in cognitive function and short term memory. AD is characterised by the formation of insoluble clumps of protein or plaques, formed by proteins known as β-amyloids. These attach to the cell surface of neurons and disabled nerve transmission. These plaques have been demonstrated to contain relatively high levels of Zn2+, Cu2+ and Fe3+ (1 mM, 0.4 mM and 1 mM respectively).(4) While the precise role of these metals is still uncertain, they appear to bind to so-called β-amyloid peptides that constitute the bulk of plaque deposits. Cu2+

Most of the lesions in the brain of an AD patient are from plaques, which consist of beta amyloid peptides that are derived from APP (amyloid precursor protein) 7. APP (amyloid precursor protein) is located on the cell membrane and consists of N extracellular terminal, short C intracellular terminal, a single hydrophobic transmembrane domain and a metal binding site 16, and there are two ways for APP cleaving (figure 2):

The majority of APP undergoes non-amyloidogenic processing via consecutive clevage by α - and γ-secretases within the Aß domain resulting in nonpathogenic fragments, sAPPa and C-terminal fragments (CTFs, (Gong et al., 2010; Vetrivel & Thinakaran, 2006). APP also undergoes sequential proteolytic cleavage by β- and γ- secretases to generate Aβ peptides, as well as, sAPPβ and CTF. The role of Aβ leading to AD was first proposed by a study in the year 1984 (Glenner & Wong, 1984). The authors hypothesized that AD is a "cerebral amyloidosis", in which cerebral β-amyloid triggers dementia and the subsequent disease etiology. This central amyloidosis thesis was later reinterpreted and reported as the “amyloid cascade hypothesis” of AD. (Glenner & Wong, 1984; Hardy & Higgins, 1992; Tanzi & Bertram,

Moreover, the complex studies of the metals (Zn & Cu) with the amyloid protein shows that the copper coordinates the amyloid beta through four or five coordinating bonds: two imidazole nitrogens from His-6 and His 13/14, one N-terminal amine nitrogen from Asp1 and a carbonyl oxygen from Ala-2. And perhaps the fifth bond is from the oxygen of Asp1 (see figure 4c) 40. But other researchers found that copper binds amyloid via His6, His13, His14, and Tyr10 (Figure 4a). After the metal binds a beta amyloid (monomeric compound) , the aggregation of β-amyloid starts after this moment by creating a new coordination bond between imidazole ring of His6 with the other copper atom from the other copper-amyloid complex to form a dimer compound (see figure 4 b)

Metal ions are essentially needed to perform a sequence of significant biological functioning in the brain, such as nerve transmission, oxygen transport, synthesis and metabolism of neurotransmitters. In recent years considerable attention has been paid to the role of transition metal ions such as Mn2+, Fe2+, Cu2+ and Zn2+ in the brain and their involvement in the neurodegenerative disorders1. Since the abnormal accumulation of these transition metal ions in the brain plays a crucial role in the pathological process such as protein aggregation and oxidative stress in the neurodegenerative disorders, which are characterized by the progressive loss of neuron structure and function which ultimately leads to neuronal death2-4. The apparent association

In this study, scientist found that there are levels of free radicals reactivity of the compounds that are being produced in the cell; some with least reactivity such as H2O2, and some are highly reactive such as OH. The free radicals can affect the cell negatively. One of the element that generates free radicals and causes oxidative stress is cadmium. It increases lipid peroxidation and/or changes intracellular glutathione levels. However, investigators found that some plants such as curcumin is a natural drug that works

High level of Aluminum in the brain causes the formation of neurofibrilar tangles (the main characteristics of the

However, (H2O2) can react with reduced transition metals, via the Fenton reaction, to produce the highly hydroxyl radical (•OH), a far more damaging molecule to the cell. In addition to forming H2O2, O2•– radicals can rapidly react with nitric oxide (NO) to generate cytotoxic peroxynitrite anions (ONOO–) (Jeffrey et al., 2003). Peroxynitrite can react with carbon dioxide, leading to protein damage via the formation of nitrotyrosine and lipid oxidation. The generation of ROS in normal cells, including neurons, is under tight homeostatic control. To help detoxify ROS, enzymatic and non-enzymatic antioxidants including speroxide dismutase (SOD), glutathione, α-tocopherol (vitamin E), catalase, will react with most oxidants. In addition, the antioxidant enzymes catalase and glutathione peroxidase detoxify H2O2 by converting it to O2 and H2O. However, when ROS levels exceed the antioxidant capacity of a cell, a deleterious condition known as oxidative stress occurs. Unchecked, excessive ROS can lead to the destruction of cellular components including lipids, protein, and DNA, and ultimately cell death via apoptosis or necrosis (Birben et al., 2012; Jeffrey et al., 2003). Indeed the World Health organization (WHO) has initiated global initiatives on neurology and public health in an effort to increase public awareness of the prevalence, severity and cost of neurological disorders with a view to identify possibilities for prevention (WHO 2006). Current