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Role of Oxidative Stress in the Onset of Alzheimer’s Disease
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Tasnuva Sarowar, Md. Hafiz Uddin
The structure of the three secretase enzymes are important. The alpha secretase comprises metalloproteases of TNFalpha and disintegrin matrix (Periz and Fortini 2000). The beta secretase or BACE (beta site APP cleaving enzyme) has different isoforms which give rise to different populations of abeta (Vassar and Citron 2000). The gamma secretase is a multiprotein complex with presenilin 1 (PSEN1), nicastrin, Aph-1, and presenilin 2 (PSEN2) (Steiner 2004). Similar to BACE, different PSEN1 and PSEN2 isoforms process APP in different manner. To generate abeta, the APP has to be cleaved by gamma and beta secretase, and various signaling pathways are associated with this. It has been shown that oxidative stress enhances beta and gamma secretase activity and increases abeta production (Tamagno et al. 2002, Oda, Tamaoka, and Araki 2010).
Drug Design, Synthesis, and Development
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
Neurodegenerative diseases, which are associated with old age will become increasingly common in the future with aging populations. Conditions such as Alzheimer’s disease result from the breakdown of normal biochemical processes in the neurones of the brain. Beta-site amyloid precursor protein cleaving enzyme (BACE), also known as beta secretase is an aspartic acid protease that is important in the formation of myelin sheaths in peripheral nerve cells. Elevated levels of this enzyme are present in patients with late-onset sporadic Alzheimer’s disease. Generation of amyloid-β peptides, which aggregate in the brain of Alzheimer’s patients to form amyloid plaques, are formed from the amyloid precursor protein (APP) after cleavage by BACE. Initial cleavage of APP by α-secretase rather than BACE prevents the eventual generation of amyloid-β, which would otherwise form the plaque which causes impaired brain function and the symptoms of Alzheimer’s. Currently, research focused on finding inhibitors of the BACE to stop the formation of amyloid plaque is ongoing. The physiological purpose of BACE is unclear, but will be a focus of Alzheimer’s research in the future.
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).
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).
Discovery and engineering of an anti-TREM2 antibody to promote amyloid plaque clearance by microglia in 5XFAD mice
Published in mAbs, 2022
Peng Zhao, Yuanzhong Xu, Xuejun Fan, Leike Li, Xin Li, Hisashi Arase, Qingchun Tong, Ningyan Zhang, Zhiqiang An
In this study, we demonstrated that TfR-mediated antibody brain delivery increased Ab2 brain concentration by more than 10-fold. Similar strategies have been exploited previously to increase brain concentrations of antibodies targeting beta-secretase 1 or amyloid plaques.40–42,44 A positive correlation between the increased antibody delivery and improved in vivo biological effects was observed in these studies.40–42,44 In comparison, all the reported TREM2 antibodies did not have brain targeting capabilities, and as a result, a much higher dose (100 mg/kg) or much more frequent dosing (twice per week) at a high dose (60 mg/kg) is required to reach effective brain concentration.18,20 Although more complex than the simple bivalent IgG, it is feasible to develop αTfR-containing tetravalent bispecific antibody therapies since bispecific antibodies using αTfR and other targeting strategies have been well studied in clinical trials.40,71–76
Brain insulin resistance: role in neurodegenerative disease and potential for targeting
Published in Expert Opinion on Investigational Drugs, 2020
Inhibition of gamma-secretase was not a successful strategy either. Semagacestat (LY-450,139) was tested in a phase III trial. 1500 patients were treated for 21 months. In 2010, the trial was halted as it showed a worsening of dementia in patients compared to placebo controls [194]. Inhibitor of beta-secretase (BACE1) did not fare any better. In June 2018, Lilly and AstraZeneca stopped a Phase 2/3 trial of 2,219 people with AD testing the BACE1 inhibitor Lanabecestat. In July 2018, Janssen stopped a Phase 2b/3 trial and a Phase 2 trial of its inhibitor Atabecestat due to liver toxicity. Nov 2018: Merck announced that in a Phase 3 trial, people with AD who took the inhibitor verubecestat scored worse on cognitive tests than those on placebo. Novartis/Amgen’s BACE inhibitor CNP520 (Umibecestat) was tested in two Phase 2/3 trials. In July 2019 the company announced that the trials have been stopped due to patients getting worse. Participants taking umibecestat declined in the RBANS cognitive composite tests, had more brain atrophy, and lost more weight than people on placebo did. In September 2019, BIOGEN and Eisai halted two phase 3 trials on the basis of safety concerns caused by their drug Elenbecestat. For details on these trials please see [195].