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β-Secretase (BACE1) Inhibitors From Natural Products
Published in Atanu Bhattacharjee, Akula Ramakrishna, Magisetty Obulesu, Phytomedicine and Alzheimer’s Disease, 2020
Formation of extracellular amyloid beta (Aβ) plaques, with drastic neuronal and synaptic reductions in the cholinergic system of the brain, is considered to be the major pathological hallmark of AD (Azimi et al., 2017; Berrino, 2002). According to the ‘beta-amyloid cascade’, deposition of the Aβ peptide triggers neuroinflammation, resulting in neurodegeneration. Aβ is derived from sequential proteolytic cleavage of the amyloid precursor protein (APP) by beta- and gamma-secretases. Initial cleavage by beta-secretase (beta-site of APP cleaving enzyme; BACE1), a membrane-anchored aspartic protease, generates a soluble N-terminal fragment and a membrane-associated C-terminal fragment. The C-terminal fragment then undergoes proteolysis by gamma-secretase to give the Aβ peptide (Skovronsky et al., 2006; Brinton et al., 1998). BACE1 has been proposed to be a promising therapeutic target as it initiates the first step in Aβ production (Barao et al., 2016). Neuroinflammation of AD likely starts as a host defense response to the damaging effects of the amyloid deposits in the brain. Hence, anti-inflammatory drugs could be another potential therapeutic target to delay progress of AD (Zhang et al., 2015).
Special considerations: Alzheimer’s disease
Published in Hemanshu Prabhakar, Charu Mahajan, Indu Kapoor, Essentials of Geriatric Neuroanesthesia, 2019
Christopher G. Sinon, Sona Shah Arora, Amy D. Rodriguez, Paul S. García
Beta-amyloid is produced following cleavage of the transmembrane protein amyloid precursor protein (APP) by beta-secretase and gamma-secretase (14). It is unclear exactly what role APP or beta-amyloid play in a normally functioning neuron, but an imbalance between the production and clearance of beta-amyloid can lead to pathologic accumulation that may play a causative role in AD (15). Tau protein is an important microtubule-associated protein that helps to stabilize the neuron's cytoskeleton by binding to microtubules (13). In vitro studies suggest that in normal cellular function the activity of tau protein is regulated by phosphorylation. When tau is phosphorylated, there is a reduction in the binding of tau to microtubules which could be an important step for the regulation of neurite outgrowth and axonal transport in the neuron. In AD, as well as all other known diseases involving dysregulated tau, there is rampant phosphorylation of tau proteins resulting in cytoskeletal abnormalities and accumulation of hyperphosphorylated tau. While neurofibrillary tangles formed from hyperphosphorylated tau can generate over decades independent of plaques or the presence of AD (16), both beta-amyloid and hyperphosphorylated tau are necessary for AD pathology.
Alzheimer's Disease
Published in Marc E. Agronin, Alzheimer's Disease and Other Dementias, 2014
Most scientists now believe that the story of AD begins with the buildup of an abnormal form of amyloid protein in the brain (Querfurth & LaFerla, 2010). This amyloid originates from part of a larger protein called the amyloid precursor protein (APP), which is normally found in the cell membranes of neurons throughout the brain. The exact role of APP has not yet been determined, although it appears to be involved in the formation and repair of synapses (Priller et al., 2006). APP is normally metabolized by a protease enzyme called alpha-secretase. In AD, however, the metabolism of APP is altered by two other enzymes, beta-secretase and gamma-secretase (also referred to as beta-site or gamma-site APP cleaving enzyme or BACE and GACE, respectively), which cleave APP, producing a protein fragment of 40 or 42 amino acids. This abnormal form of amyloid is referred to as beta-amyloid (denoted hereafter in the text as Ab). The 40–amino acid variant (Ab40) is more common, but the 42–amino acid variant (Ab42) appears more pathologic, especially in early-stage AD. Once Ab is formed, however, it self-aggregates into soluble oligomers consisting of two to six peptides (which may further group together) or into fibrils, which have a tendency to accumulate into insoluble beta-pleated sheets. These various forms of Ab build up in the brain in the spaces between neurons and in small blood vessels (Walsh & Selkoe, 2007).
Natural inhibitors for acetylcholinesterase and autophagy modulators as effective antagonists for tau and β-amyloid in Alzheimer’s rat model
Published in Biomarkers, 2023
Mervat Hassan, Hisham Ismail, Olfat Hammam, Abdullrahman Elsayed, Othman Othman, Sohair Aly Hassan
Physiologically, tau is a microtubule-associated protein that modulates microtubule stability and axonal transport (Kadavath et al. 2015). Tau is a natively unfolded protein with a low aggregation tendency and is extremely soluble. Nevertheless, tau aggregation is a hallmark of a plethora of neurodegenerative disorders, including Alzheimer’s disease (Hassan and Kadry 2021). Accordingly, in the current study tau, β-amyloid, (AchE) levels were significantly elevated, while (Ach) was markedly reduced in the intoxicated model compared to the normal at (P < 0.0001). It was not surprising that the intoxicated group had been exposed to strong oxidative stress agents (150 & 300 mg/kg AlCl3 and D-gal respectively), which participate in a series of activation mechanisms. First, activation of phosphorylated enzymes which increased the tendency of tau for more aggregation. Second, activation of beta-secretase which increased the breakdown of amyloid precursor protein (APP) and encouraged more deposition of amyloid-beta (Aβ) plaque on the brain cells. Lastly, activation of acetylcholinesterase which led to more breakdown of the acetylcholine, the important neurotransmitter for the neuron. All consequences ultimately led to an impairment in cognitive memory. These modifications occur due to Al being a powerful cholinotoxin that influences the blood-brain barrier, causing changes in noradrenaline and cholinergic neurotransmission (Yokel 2000), whereas D-gal enhances AchE activity in the brain of rats (Rodrigues et al. 2017).
Assessing the role of Porphyromonas gingivalis in periodontitis to determine a causative relationship with Alzheimer’s disease
Published in Journal of Oral Microbiology, 2019
The insoluble Aβ deposits (amyloid plaques) in the AD brain [37] are the consequence of amyloid precursor protein (APP) proteolysis along the N terminus (start of the protein) to the cytoplasmic tail at the C terminus (end of the amino acid chain terminated by a free carboxyl group). The enzymes generating Aβ are known as beta-secretase 1 or BACE 1, which couples with γ-secretase in the familial form of AD [38–40]. BACE 1 in this context therefore, recognizes the cleavage site of the mutated (mt)APP gene in the familial form of AD and results in enhanced Aβ production [41]. This genetic trait is the basis for generating transgenic mouse models for evaluating human AD. However, APP in the sporadic form of AD is not mutated [42], and the results of infections can vary according to the genetic make-up of the host animal. This fact has to be considered by researchers when selecting animal models to test their hypothesis and by readers when comparing experimental outcomes. Whilst, Aβ40 is the most prominent species (80–90 %) found in AD brains, the amyloidogenic Aβ42, overall represents the lesser component (5–10 %) [37,43]. Other species of Aβ fibrils (Aβ39, 38, 34, 33) also occur in the AD brain but their presence is generally neglected [44] for reasons poorly understood.
Effect of flavonoids rich extract of Capparis spinosa on inflammatory involved genes in amyloid-beta peptide injected rat model of Alzheimer's disease
Published in Nutritional Neuroscience, 2018
Nazanin Mohebali, Seyed Abolhassan Shahzadeh Fazeli, Hossein Ghafoori, Zeinab Farahmand, Elham MohammadKhani, Faezeh Vakhshiteh, Abdolreza Ghamarian, Mansoureh Farhangniya, Mohammad Hossein Sanati
Alzheimer's disease (AD) is known to be one of the most common chronic neurodegenerative diseases with pathological hallmarks of neuritic plaque and neurofibrillary tangles. These hallmarks are respectively related to the aggregation of the amyloid-beta peptide (Aβ) in brain tissue, and hyperphosphorylation of microtubule-associated tau protein in neurons.1 Several genetic and environmental factors are considered to be involved in amyloidogenic process. AD occurs as a result of Aβ peptide aggregation, which itself is caused by any mutation or malfunction in gamma- and beta-secretase enzymes. Any structural or functional alteration in genes encoding these two enzymes or their subunits could lead to Aβ aggregation. Gamma-secretase enzyme is consisted of four subunits including presenilin 1 and presenilin, which are encoded by PSEN-1 and PSEN-2, respectively. Beta-secretase enzyme is encoded by BACE-1 gene. These two enzymes are responsible for the cleavage of APP, which is the amyloid protein precursor.