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Treatment Of Alzheimer’s Disease
Published in Zaven S. Khachaturian, Teresa S. Radebaugh, Alzheimer’s Disease, 2019
Lina Shihabuddin, Kenneth L. Davis
AD is characterized by neurofibrillary tangles and extracellular deposits of amyloid beta protein (AB). AB, which constitutes the plaques, has been implicated in cell death (Hardy and Higgins, 1992; Wisniewski et al., 1991). AB is derived from processing of the transmembrane amyloid precursor protein (APP)(Goldgaber et al., 1987; Kang et al., 1987; Robakis et al., 1987). Lysosomal processing of APP may produce amyloidogenic fragments (Estus et al., 1992; Golde et al., 1992; Haass et al., 1992). Thus, agents interfering with AB production and/or toxicity could have a beneficial effect in altering the course of AD. The effects of colchicine and hydroxychloroquine on lysosomal processing suggest that these agents are candidates for clinical trials in AD. Cholinergic agonists were shown to alter the processing of the amyloid precursor protein by increasing the secretory breakdown pathway of the protein (Buxbaum et al., 1992). Thus, manipulation of the cholinergic activity may have its beneficial effect in AD not only through augmentation of cholinergic neurotransmission but also through interfering with amyloid deposition.
Historical concepts of Alzheimer’s disease and dementia
Published in Howard H. Feldman, Atlas of Alzheimer's Disease, 2007
Jacob Grand, Howard H. Feldman
In 1984, Glenner and Wong18 reported the amino acid sequence of the main component of β-amyloid, a 4-kDa peptide termed ‘amyloid beta protein’ (Aβ) (Figure 1.17b). Subsequently, the gene encoding the amyloid precursor protein (APP) was isolated and mapped to chromosome 2119 (Figure 1.17c). The discovery of autosomal dominant mutations in APP heralded numerous breakthroughs in the genetics of AD. This impacted not only the small number of identified families, but also the subsequent elucidation of the secretases which process APP and the β-amyloid core. In the mid-1990s genetic linkage studies uncovered mutations in presenilin 1 (PSEN1) on chromosome 14,20 and presenilin 2 (PSEN2) on chromosome 1.21 Presenilin forms the active site of the γ-secretase complex involved in the production of Aβ (Figure 1.17d). Cleavage of APP by γ- and β-secretases produces the Aβ peptide which aggregates into plaques (Figure 1.17e). To date, a total of 16 autosomal-dominant mutations of APP have been found, 140 in PSEN1 and 10 in PSEN2.22
Phytotherapeutic Potential For the Treatment of Alzheimer’s Disease
Published in Atanu Bhattacharjee, Akula Ramakrishna, Magisetty Obulesu, Phytomedicine and Alzheimer’s Disease, 2020
Muhammad Akram, Atanu Bhattacharjee, Naveed Munir, Naheed Akhter, Fozia Anjum, Abida Parveen, Samreen Gul Khan, Muhammad Daniyal, Muhammad Riaz, Fahad Said Khan, Rumaisa Ansari, Umme Laila
Alzheimer’s disease (AD) is defined as a profound loss of memory that may disturb a person’s occupational and social life, or even the simple daily tasks. AD was first described by German physician Alois Alzheimer in 1906. It occurs mostly in old age, and 50–60% cases of dementia present with AD (Francis, Palmer et al. 1999). It affects 5% of the population, according to the Center for Disease Control and Prevention. AD is a condition in which the patient presents with episodes of memory loss and it leads to dementia. This occurs because the temporal lobe of the brain becomes atrophied, after it has spread to the frontal, temporal and parietal lobes completely (Klunk, Engler et al. 2004). In the brain, amyloid-beta neuritic plaques are found with neurofibrillary tangles, and amyloid-beta protein also accumulates in vessels of the cortex and meninges (Perl 2010). AD is a neurodegenerative, progressive, and multifactorial disorder that occurs largely in old age, with 50–60% of cases of AD occurring in patients over 65 years of age (Francis, Palmer et al. 1999; Adams, Gmünder et al. 2007). A decrease in the level of neurotransmitter chemical acetylcholine, due to neural degeneration, is a neuro-pathological feature (Howes and Houghton 2003; Zhang 2004). AD occurs in both sporadic and familial forms. Mutations occur in the genes encoding amyloid precursor proteins and presenilin 1 and 2 (Selkoe 2001). The familial disease consists of 2–3% cases of AD (Selkoe and Schenk 2003), whereas sporadic AD occurs in the majority of elderly patients with AD aged above 65 years, and the cause is unknown (Selkoe 2001). The sporadic disease is associated with many factors, including aging (Selkoe 2001), defects in mitochondria (Bertram and Tanzi 2008), and diabetes mellitus (Reddy, Mani et al. 2005; Tanzi and Bertram 2005). It is also triggered by certain environmental factors (de la Monte and Wands 2005). Sporadic AD can be induced by diet (Lazarov, Robinson et al. 2005; Qiu and Folstein 2006). The familial disease, on the other hand, is due to gene mutations which accelerate its development (Selkoe 2001). In the sporadic disease, cellular changes control the disease and do not occur as a result of gene mutations (Reddy, Mani et al. 2005). Studies of the cellular, molecular, and histopathological features of AD shows that it is due to multiple reasons (Reddy and Beal 2005). It is caused by amyloid plaque formation, neurofibrillary tangles, and disturbance in the levels of neurotransmitter chemicals (Selkoe 2001).
Privileged multi-target directed propargyl-tacrines combining cholinesterase and monoamine oxidase inhibition activities
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Zofia Chrienova, Eugenie Nepovimova, Rudolf Andrys, Rafael Dolezal, Jana Janockova, Lubica Muckova, Lenka Fabova, Ondrej Soukup, Patrik Oleksak, Martin Valis, Jan Korabecny, José Marco-Contelles, Kamil Kuca
To gain further insight into the mechanism of hAChE inhibition, an enzyme kinetic study was performed on the most potent AChE inhibitor of the series (23). The graphical presentation of the steady-state inhibition data of compound 23 for hAChE is demonstrated in Figure 1. The analysis of the direct plots revealed a reduction of Vmax, whereas Km remained unchanged. These findings are consistent with a non-competitive mode of enzyme inhibition. In case of AChE, it means that the preferential binding site of propargyltacrines is the peripheral anionic site (PAS). From the perspective of AD therapy, this is a highly desirable effect since aggregation of amyloid-beta protein (Aβ) and subsequent neurotoxic cascade are catalysed particularly by the PAS of AChE39. Replots of the slope versus concentration of 23 gave an estimate of the competitive inhibition constant (Ki) of 12.39 ± 1.40 nM, which is consistent with the IC50 (hAChE) value obtained above.
Genetic analysis of Vietnamese patients with early-onset Alzheimer's disease
Published in International Journal of Neuroscience, 2022
Trang Mai Tong, Thuy Thi Hong Dao, Loc Phuoc Doan, Dat Thanh Nguyen, Quynh-Tho Thi Nguyen, Thanh-Thuy Thi Do, Kiet Dinh Truong, Minh-Duy Phan, Hoai-Nghia Nguyen, Thang Cong Tran, Hoa Giang
Alzheimer's disease (AD) is the most common neurodegenerative disorder in dementia and poses a major challenge to public health worldwide. Genetic predisposition is a known risk factor for AD and contributes to two subgroups: early-onset and late-onset Alzheimer's disease (EOAD and LOAD) [1]. While EOAD is less prevalent (5% of all AD cases), its molecular mechanism is better characterized than that of LOAD [2]. Original studies in the 1990s had showed that few mutations of amyloid-beta protein precursor (APP) gene were associated with familial AD [3, 4]. Following studies in APP protein processing had identified mutations in amyloid-beta protein precursor (APP), presenilin-1 (PSEN1), presenilin-2 (PSEN2) genes as the main cause of EOAD development [5, 6].
Polyamine biomarkers as indicators of human disease
Published in Biomarkers, 2021
Mohsin Amin, Shiying Tang, Liliana Shalamanova, Rebecca L. Taylor, Stephen Wylie, Badr M. Abdullah, Kathryn A. Whitehead
In current practice, the presence of AD is confirmed through measurements of amyloid-beta protein, tau protein and phospho-tau levels in the patient’s cerebrospinal fluid (Figure 6) (Galimberti and Scarpini 2010, Sharma and Singh 2016). Neurofibrillary tangles are a fundamental pathological hallmark of AD and are aggregates of hyperphosphorylated tau protein (Serrano-Pozo et al.2011). Tau protein is a microtubule-binding protein that is mainly expressed in neurons (Stoothoff and Johnson 2005). The hyperphosphorylation of this protein is what is thought to be one of the causes of tau dysfunction, causing binding to the microtubules in the neurons, leading to the eventual disruption of the neuronal microtubules with subsequent impairment of axoplasmic flow and loss of neuronal connectivity (Grundke-Iqbal et al.1986, Iqbal et al.2000, Blennow and Zetterberg 2018). Studies have suggested that the pathological severity of AD is at its greatest during the early stages of the disease. Due to the invasive nature of current diagnosis and treatment strategies, research aims are focusing towards alternate biomarker sources thus, aiming at slowing the progression of neurodegeneration (Thalhauser and Komarova 2012, Nelson and Tabet 2015, Folch et al.2016).