Common Factors Of Alzheimer’s Disease And Rheumatoid Arthritis—Pathomechanism And Treatment Part 1

Abstract: 

The accumulation of amyloid plaques, or misfolded fragments of proteins, leads to the development of a condition known as amyloidosis, which is clinically recognized as a systemic disease. 

Amyloid plaques are a common pathological phenomenon in the elderly. They manifest as abnormal amyloid deposition in brain tissue, which can seriously affect the memory and cognitive ability of the elderly. However, we should maintain a positive attitude because there are many ways to alleviate and reduce the impact of amyloid plaques on memory.

First, moderate exercise is an effective method. Studies have shown that moderate aerobic exercise can improve memory and cognitive ability. For the elderly, you can choose low-intensity exercise such as walking, skipping rope, swimming, etc., three to five times a week, more than 30 minutes each time.

Secondly, maintaining social activities is also an effective method. The elderly are often troubled by loneliness and depression, which can cause a lot of stress and anxiety, thereby accelerating the growth of amyloid plaques. Talking with friends, participating in community activities and volunteering are all very good social activities that can improve the quality of life and physical and mental health of the elderly.

In addition, a reasonable diet is also very helpful in alleviating the impact of amyloid plaques. Choose a variety of nutritious foods as much as possible, such as fruits, vegetables, nuts, and fish. At the same time, avoid excessive intake of fat and sugar, because these foods will accelerate the formation of amyloid plaques.

In conclusion, the relationship between amyloid plaques and memory loss in the elderly does exist, but we should maintain a positive attitude and take measures to mitigate its impact. Through moderate exercise, social activities, and a reasonable diet, the elderly can maintain a healthy body and mind and a good quality of life. This shows that we need to improve memory, and Cistanche can significantly improve memory because Cistanche is a traditional Chinese medicinal material with many unique effects, one of which is to improve memory. The efficacy of Cistanche comes from the various active ingredients it contains, including tannic acid, polysaccharides, flavonoid glycosides, etc. These ingredients can promote brain health in a variety of ways.

Click Know Ways to Improve Memory

Amyloidosis plays a special role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease, and rheumatoid arthritis (RA). 

The occurrence of amyloidosis correlates with the aging process of the organism, and since nowadays, old age is determined by the comfort of functioning and the elimination of unpleasant disease symptoms in the elderly, exposure to this subject is justified. 

In Alzheimer's disease, amyloid plaques negatively affect glutaminergic and cholinergic transmission and loss of sympathetic protein, while in RA, amyloids stimulated by the immune system's activity affect the osteoarticular bond's degradation. 

The following monograph draws attention to the over-reactivity of the immune system in AD and RA, describes the functionality of the blood-brain barrier as an intermediary medium between RA and AD, and indicates the direction of research to date, focusing on determining the relationship and the cause-effect link between these disorders. 

The paper presents possible directions for the treatment of amyloidosis, with particular emphasis on innovative therapies.

Keywords: Alzheimer's disease; rheumatoid arthritis; amyloid; immune system.

1. Amyloid Plaques, Structure, Importance, Factors Predisposing to Their Appearance

Amyloidosis is a disease associated with the extracellular accumulation of misfolded protein fragments [1]. Amyloid proteins are characterized as "chameleon proteins" due to their characteristic ability to adopt several conformations [2]. 

It should be noted that all amyloid proteins are unbranched and have a diameter of 70 to 120 Å [3]. The first studies on isolated amyloid fibrils concerned the knowledge of their structure. X-ray diffraction studies have shown that amyloid-like proteins have a cross-structure β [4,5]. Later studies using NMR analysis further confirmed this hypothesis [6]. 

Due to the ubiquitous presence of proteins in the body's cells, amyloidosis is clinically considered a systemic disease [7]. For example, amyloid accumulation plays a special role in the pathogenesis of Alzheimer's disease (AD), Parkinson's disease, or transthyretin amyloidosis [8]. Protein abnormal folding, characteristic of amyloidosis, most often concerns the transthyretin protein (TRT) and the immunoglobulin light chain [9]. 

In amyloidosis, a protein acquires an abnormal structure through a variety of mechanisms. One of them is that the protein has a naturally intrinsic tendency to adopt a pathological structure that becomes visible with age. The present situation occurs in senile systemic amyloidosis [10]. 

A separate mechanism is that substitution results in replacing a single amino acid with another, which predisposes to the emergence of hereditary amyloidosis [11]. The last mechanism concerns the proteolytic remodeling of the precursor protein [12]. 

Amyloid is a structure that occurs in the form of insoluble and pathological deposits. The most common component of the deposits is the SAP (serum amyloid P) glycoprotein, belonging to the pentraxin family, which after radioactive labeling becomes a diagnostic tool for imaging the presence of pathological proteins [13]. 

The SAP glycoprotein is protected against proteolysis, and this property ensures its resistance to degradation [14]. Proteoglycans are also a component of amyloid that exhibit similar cell deposition kinetics as fibrillar proteins. Moreover, they are located in the vicinity of specific structures of the extracellular matrix such as perlecan, laminin, entactin, and collagen IV [15]. 

Amyloid accumulation is dependent on several factors. High local protein concentration, low pH in the cell, and the presence of filamentous seeds predispose to the accumulation of pathological deposits. 

The presence of specific receptors on the cell surface additionally influences amyloid deposition. RAGE receptors are such receptors-the receptor for advanced glycation end-products, which is the receptor for A-β [16]. 

The current research work aims to show how amyloid contributes to tissue damage and organ dysfunction. The most common theory explores that the presence of amyloid conglomerates disrupts the proper functioning of structures in its vicinity. The pressure exerted by the amyloid becomes a direct cause of degeneration of the tissues and organs in the vicinity of the amyloid. 

It is worth mentioning that the accumulation of proteins with an abnormal structure leads to the disturbance of the organism's homeostasis [17]. The initiation process of amyloid formation is related to the human biological clock (especially with old age), genetic mutations, modifications after protein synthesis, or it results from an increased concentration of amyloidogenic precursor [18]. 

Many scientific works emphasize the search for links between the aging process of the body and the occurrence of amyloidosis. It is known that the risk of developing amyloidosis increases with age. 

The aging of the organism predisposes to the appearance of amyloid in tissues and organs and is also a signal for the deposition of proteins with a pathological structure [19]. The above dependence is related to the importance of the protostatic process, which fluctuates with age. 

The main importance of this process lies in maintaining the proper concentration of proteins in cells, their spatial structure, and their subcellular localization [20]. It should be pointed out that the aging of the organism initiates the deposition of amyloid precursor proteins such as amyloid β (Aβ), tau, or α-synuclein, the presence of which is associated with the pathology of Alzheimer's or Parkinson's disease [21]. 

Furthermore, one must mention that for the fibrillation process, it is necessary to have a sufficient amyloidogenic potential of the protein and the achievement of a critical local concentration by the protein precursor. 

The initiation process can be enhanced by the above-mentioned factors and the interactions of the protein with extracellular matrices [22].

The most commonly deposited pathological proteins are transthyretin (TRT), islet amyloid polypeptide (IAPP), atrial natriuretic factor (ANF), apolipoprotein AI (ApoAI), and the recently discovered fibulin-like substance containing epidermal growth factor: extracellular matrix protein 1 (EFEMP1) in the extracellular matrix1 (EFEMP1) people, APrP (Prion protein, wild type), ACal ((Pro)calcitonin), ASem1, Semenogelin 1, and huntingtin [23,24]. 

The authors resigned from a detailed discussion of all pathological proteins. However, it should be noted that AD and RA discussed in the work are diseases with amyloid pathology, which required an introduction to this topic. 

Moreover, a lot of previous scientific works on amyloidosis have mainly focused on the pathology of amyloid in Alzheimer's disease [25]. However, in the field of recent research, it has been noted that amyloidosis is a disorder involving many tissues and organs. 

In these studies, the existence of cause-effect relationships between amyloid accumulation and the occurrence of metabolic diseases, cardiovascular diseases, and skeletal system disorders have been reported [26] (Table 1). 

The main determinant of research on amyloid is the need to determine the relationship between the aging process of the body and the predisposition to the accumulation of pathological proteins. 

Exploring similar topics is justified, since life expectancy is longer, and nowadays, old age is determined by the comfort of functioning or the elimination of unpleasant symptoms of diseases accompanying the elderly [27].

Amyloid accumulation takes place throughout the body: in the central and peripheral nervous system and many organs: the heart, kidneys, and the bone and joint system [29]. 

The literature describes many types of systemic amyloidosis, four of which are seen most frequently: AL (immunoglobulin light chain amyloidosis), AA (also known as secondary amyloidosis), ATTR (transthyretin amyloidosis), and Aβ2M (Beta-2 Microglobulin amyloidosis) [30]. These amyloidoses are described in Table 2.

2. Amyloid Plaques in AD and RA

AD is a disorder of the nervous system, and according to the estimates of the World Report on Alzheimer's disease, in 2050, its worldwide incidence will exceed 152 million people [35]. Alzheimer's disease is a neurodegenerative disease [36]. 

According to the ICD10 classification, it is defined as a progressive disorder characterized by the degradation of nerve cells [37]. Loss of neurons in memory regions of the brain causes dementia-like changes. 

Neurodegeneration correlates with the deterioration of cognitive functions, which, with the progression of the disease, significantly limits the efficient functioning of patients. Moreover, changes in the upper levels of the central nervous system (CNS) cause changes in the patient's behavior or the emergence of psychiatric disorders [38]. 

In terms of neurophysiology, Alzheimer's disease is associated with the appearance of two pathological structures in the brain tissue structures: extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs). 

The appearance of the above structures contributes to the occurrence of nerve cell atrophy [39,40]. The process of Aβ peptide formation, which is a disease marker, is related to the enzymatic cleavage of the amyloid precursor protein (APP) [41]. 

APP alternates in two ways, with two different cutting paths. In the non-amyloidogenic pathway, APP is cleaved by α- and γ-secretase to form Aβ17-40/42 peptide or Aβ1-16 peptide. On the other hand, in the case of the amyloidogenic pathway, APP is cleaved sequentially by β- and γ-secretases, leading to the formation of full-length β peptide A (mainly Aβ1-14/42) [42]. 

Although Aβ1- 40 is present in much greater amounts in the brain, Aβ1-42 is a less soluble form and is more prone to accumulate. The accumulation process leads to the formation of conglomerates, which are referred to in the literature as oligomers. 

The above structures are rearranged into protofibrils and filaments, having their organization in amyloid plaques [43]. One hypothesis is that soluble fibril precursors adopt a specific quaternary conformation that exhibits significant cytotoxicity that is largely unknown at present. The stimulation of oxidative stress mechanisms dictates cellular toxicity and additionally assumes the activation of cellular apoptotic pathways. 

Moreover, the aforementioned hypothesis indicates that mature, fibrillar amyloid deposits are inactive reservoir structures in balance with less toxic syndromes [44]. The presence of pathological plaques affects the neurotransmitter systems, especially the glutamatergic system. 

In this system, the main neurotransmitter is glutamate, which plays a key role in the process of creating memory engrams. The activity of glutamate comes down to its mediation in learning and memory processes. 

The activity of glutamate is related to the second type of messenger, calcium ions (Ca2+), which help to create the chemical environment necessary for information gathering [45]. Under pathological conditions, excess glutamate causes an excessive intracellular influx of calcium ions, which in turn leads to calcium overload. In an environment of excessive calcium presence, nerve cells die [46]. 

In Alzheimer's disease, Aβ plaques cause extracellular accumulation of glutamate and intracellular deposition of calcium ions. Non-fibrillar oligomers, which are likely present in higher concentrations near amyloid plaques, can also disrupt calcium homeostasis [47,48]. Therefore, it is worth noting that Aβ plaques increase the susceptibility of neurons to excitotoxicity and loss of synaptic protein [49]. 

In Alzheimer's disease, the dysfunction of cholinergic transmission in the forebrain is also observed. In patients with Alzheimer's disease, the depleted presynaptic presence of cholinergic markers has been detected in the areas of the cerebral cortex, and it has been shown that the Meynert basal nucleus (NBM) located in the basal forebrain undergoes neurodegeneration as the disease progresses [50,51]. 

The loss of neurons in the forebrain and limbic system leads to dysfunctional changes in nicotinic receptors with a decrease in their density in the cerebral cortex and influences the activity of muscarinic receptors in the cerebral cortex [52,53]. 

The cholinergic neurons of the forebrain are the cells with the greatest neurodegenerative potential and also the structures most susceptible to the formation of neurofibrillary tangles [54]. 

The impoverishment of cholinergic transmission is caused by the presence of amyloid, and this relationship correlates with the negative effect of senile plaques on choline acetyltransferase, which participates in the synthesis of acetylcholine [55]. Studies in animal models have shown that cholinergic loss results in increased accumulation of Aβ and tau protein [56]. 

Based on other studies, it is determined that disturbances of cholinergic transmission in the brains of rats induce pro-inflammatory mechanisms and influence the disclosure of cognitive disorders [57]. 

Acetylcholine, being a neurotransmitter of the cholinergic system, additionally affects the functionality of the blood-brain barrier. It has been argued that the loss of cholinergic transmission potentially contributes to abnormalities in the diffusion and transport of metabolites between the interstitial fluid and the cerebrospinal fluid. Impairment of substance exchange across the blood-brain barrier impairs the clearance of Aβ from the brain [58]. 

It has also been shown that defective cholinergic transmission affects the continuity of the blood-brain barrier and thus disrupts the perivascular clearance of Aβ [59]. It should be noted that the accumulation of amyloid beta begins in other parts of the brain. 

Based on the research of Palmqvist et al. [60], it is known that the accumulation of Aβ fibrils begins in certain regions of the brain before they can be found throughout the neocortex, and before neurodegeneration is present. The researchers described that the early stages of amyloid deposition take place in the precuneus, posterior cingulate cortex, and orbitofrontal cortex. 

When examining subjects with even earlier signs of Aβ accumulation (CSF (cerebrospinal fluid)−/PET (positron emission tomography)− subjects who converted to CSF+/PET− within 2 years), a significantly increased Aβ fibril accumulation rate was again seen in the medial orbitofrontal and posterior cingulate cortex compared with stable CSF−/PET− subjects [60]. 

Braak [61] described the tau pathology progression from locus coeruleus through the transentorhinal region to cortical areas. These data suggest that tauopathy associated with sporadic Alzheimer's disease may begin earlier than previously thought and possibly in the lower brainstem rather than in the transentorhinal region [61]. 

In recent years, scientific works examining the influence of peripheral processes on the pathomechanism of nervous system diseases have gained great value. In AD, it refers to the influence of the immune system on the onset of the disorder, which is the inflammatory basis of the disease. Thus, according to the literature, immunological mechanisms are responsible for the occurrence of dementia-like disorders [62]. 

The inflammatory reaction within the central nervous system is mediated by microglial cells. The activated microglia produce pro-inflammatory cytokines such as TNF-α (tumor necrosis factor-α), IL-1 (interleukin-1), IL-6 (interleukin-6), and chemokines. 

The above mediators of the inflammatory reaction initiate the process of chronic inflammation within the nervous system, leading to the death of neurons and the intensification of neurodegenerative changes [63–65]. The relationship of Aβ with the inflammatory theory is justified because senile plaques intensify the production of free radicals and initiate the cascade of inflammatory processes [66]. 

This is due to the presence of microglia near senile plaques and neurons containing neurofibrillary tangles, which, when mobilized, constitute an immunological line of defense [67,68]. Mobilized microglia can show a twofold phenotype depending on the environment. 

The protective function of microglia becomes apparent when Aβ fibers or neuronal debris are removed or when it is involved in synaptic remodeling and the release of growth factors. In contrast, the neurotoxic phenotype stimulates the activity of cytokines such as TNF-α and IL-1β (interleukin 1β). These immune system mediators cause tissue damage and disease progression [69]. 

The accumulation of Aβ starts in the preclinical phase of AD, leading to the progression of degenerative changes within ten years. In the prodromal phase of the disease, amyloid activity shows a potential for a plateau. 

At this time, mild cognitive impairment (MCI) becomes apparent [70]. In the prodromal phase of the disease, hyperphosphorylation of the tau protein occurs alongside its aggregation into neurofibrillary tangles. 

This response contributes to direct neuronal dysfunction and contributes to the progression of dementia and progressive dementia [71]. RA is defined as a degenerative disease of the skeletal system. 

The disorder is characterized by the presence of a systemic inflammatory reaction that affects articular cartilage and bones [72]. Normally, the disease process involves immune cells that cascade to engage subsequent cells and mediators. Involvement of the immune system is associated with the activation of appropriate cells, resulting in the release of matrix metalloproteinases (MMPs) and inflammatory cytokines [73]. 

Ultimately, the ongoing processes result in the occurrence of painful joint swelling and impairment of their functions [74]. The factors that predispose to RA are not clearly explained. It has been suggested that the disease is related to genetic and exogenous factors. 

The first cells involved in the pathogenesis of RA are CD4+ lymphocytes. These cells recognize antigens in the synovial tissue and stimulate monocytes, macrophages, and synovial fibroblasts. 

The abovementioned cells secrete metalloproteinases that are involved in the erosion of cartilage and bone. In addition to their degradative activity, these immune cells are involved in the production of interleukin (IL)-1, IL-6, and TNF-α, which are responsible for the key inflammatory response in RA. The entire cascade process eventually leads to synovitis, which becomes thickened and enlarged [75].

For more information:1950477648nn@gmail.com