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Elevated Cytosolic Phospholipase A2α as a Target for Treatment and Prevention the Progression of Neurodegenerative Diseases
Published in P. Mereena Luke, K. R. Dhanya, Didier Rouxel, Nandakumar Kalarikkal, Sabu Thomas, Advanced Studies in Experimental and Clinical Medicine, 2021
Rachel Levy, Yulia Solomonov, Kesenia Kasianov, Yafa Malada-Edelstein, Nurit Hadad
Behavioral deficit was detected by reduction in spontaneous behavioral alterations using a Y-maze analysis at 8 weeks of Amyloid beta1–42 (Aβ) brain infusion. Prevention of elevated cPLA2α protein expression by brain infusion of AS with Aβ, prevented the behavioral deficit in comparison with none treated mice or mice treated with sense. Brain infusion of AS alone did not have a similar effect on mice behavior analyzed by Y-maze.
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).
What Actually Is Sleep?
Published in Zippi Dolev, Mordechai Zalesch, Judy Kupferman, Sleep and Women's Health, 2019
Zippi Dolev, Mordechai Zalesch, Judy Kupferman
The toxin clearance mechanism active during sleep is known as the “glymphatic system,” like the lymphatic system that clears toxic matter throughout the entire body. To date, the mechanism has been seen in mice and baboons; however, researchers have good reason to assume that the same process also occurs in human brains. One of the proteins that accumulates in the brain during the hours of daily activity is amyloid beta, known to cause Alzheimer's disease. Alzheimer's and other dementia diseases have also been found to be connected to sleep disorders. This has led scientists to assume that Alzheimer's and other neurological diseases are caused by unsatisfactory functioning of the toxin-cleansing process during sleep time. This can explain why we do not think clearly after a sleepless night, and why a lack of sleep over a period of time can cause death. So, if brain cleaning is a lifesaver, or at least a life preserver, why does it occur only during sleep? Why not perform toxin cleaning more frequently? Professor Nedergaard suggests that the cleansing process demands a huge amount of energy: “It is probably impossible for the brain to self-clean and at the same time to be aware of the surroundings, to talk, move, etc.”
An insight into the neuroprotective effects and molecular targets of pomegranate (Punica granatum
) against Alzheimer’s disease
Published in Nutritional Neuroscience, 2023
Namy George, Majed AbuKhader, Khalid Al Balushi, Bushra Al Sabahi, Shah Alam Khan
Alzheimer’s disease (AD) is one of the most typical neurodegenerative diseases that reduce the quality of life of the patients by causing cognitive impairment and in turn causes difficulties in performing day to day activities of life [1]. Currently, the drugs prescribed in AD are used to control memory loss, cognitive effects of AD and behavioral changes of the disease. These drugs only offer a symptomatic treatment and are inefficient in halting the progression of the disease [2]. Furthermore, their continuous usage leads to many adverse effects. Therefore, there is an urgent requirement in the intervention of the current treatment regimen to modify some of the risk factors causing the disease and also to prevent the progression and improve the quality of life of the patients. Investigation of AD-affected brain shows an accumulation of amyloid-beta (Aβ) and tau proteins. Many pieces of evidence show that the cholinesterase enzymes are responsible for the accumulation of amyloid peptides resulting in the formation of plaques [3]. Hence, acetylcholinesterase (AChE) enzyme is one of the main targets in the treatment of AD. Vascular diseases, neuronal plasticity, chronic inflammation, imbalance in the generation and clearance of reactive oxygen species (ROS), activation of stress kinase pathway excessive phosphorylation of tau proteins are some of the other factors responsible for the development of AD [4].
Focusing on oligomeric tau as a therapeutic target in Alzheimer’s disease and other tauopathies
Published in Expert Opinion on Therapeutic Targets, 2023
Moving forward, the key steps are to identify pathogenic, as opposed to merely pathological, form(s) of tau, and then rigorously assess their potential as drug targets. Coincidentally, an important lesson can be applied from recent efforts to develop immunotherapies against amyloid beta in AD. In particular, Lecanemab is selective for toxic forms of amyloid beta, and has produced statistically meaningful signals in clinical trials [86–88]. By comparison, clinical trials for earlier generation immunotherapies that indiscriminately target amyloid beta species have been spectacularly unsuccessful. Likewise, a growing body of evidence points to oligomeric tau as a major pathogenic species, distinct from other tau conformations, and one that deserves further attention as a therapeutic target. Simply stated, not all forms of tau (or amyloid beta) are bad. Drug development efforts should focus on structural configurations that may actively drive pathology.
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).