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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).
Micronutrients in the Prevention and Improvement of the Standard Therapy for Alzheimer’s Disease
Published in Kedar N. Prasad, Micronutrients in Health and Disease, 2019
It is now established that beta-amyloid fragments (Aβ1-42) generated by the cleavage of APP play a central role in the pathogenesis of AD.12,13,40,180 There are two pathways of processing of APP in the neurons. The predominant pathway of APP processing consists of successive cleavages by alpha- and gamma-secretases, whereas the other pathway involves sequential cleavage of APP by beta- and gamma-secretases. It is the latter pathway that generates neurotoxic beta-amyloids. Normally, alpha-secretase cleaves inside beta-amyloid sequence of APP, releasing the soluble N-terminal domain of APP that exhibit neurotrophic and neuroprotective properties. In patients with AD, a decrease in alpha-secretase-mediated processing of APP has been found in the autopsied brain samples.181 This process would allow accumulation of APPs, which are cleaved by beta- and gamma-secretase to produce beta-amyloids.
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).
Antihypertensive agents in Alzheimer’s disease: beyond vascular protection
Published in Expert Review of Neurotherapeutics, 2020
Thibaud Lebouvier, Yaohua Chen, Patrick Duriez, Florence Pasquier, Régis Bordet
Inhibition of amyloidogenesis is the second putative effect of CCBs. In primary cultures expressing human APP, a sustained high concentration of cytosolic calcium inhibited the alpha-secretase cleavage of APP (non-amyloidogenic pathway) and induced the production of intraneuronal Aβ42 (amyloidogenic pathway), a process that was prevented by nimodipine [82]. The latter is controversial since nimodipine was shown to increase Aβ42 production and secretion in a different culture setting [78,83]. Paris et al. showed that among several L-type CCBs, only nilvadipine and to a lesser extent nitrendipine were able to lower Aβ production, independently of their action on L-type calcium channels. This effect might be due to inhibition of the spleen tyrosine kinase Syk, which indirectly inhibits the β-cleavage of APP [78,84].
Folic acid increases levels of GHS in brain of rats with oxidative stress induced with 3-nitropropionic acid
Published in Archives of Physiology and Biochemistry, 2020
David Calderón Guzmán, Norma Osnaya Brizuela, Maribel Ortiz Herrera, Hugo Juárez Olguín, Armando Valenzuela Peraza, Ernestina Hernández García, Gerardo Barragán Mejía
Cerebral folate deficiency is defined as any neurological condition associated with low cerebrospinal fluid folate concentrations. Presently, several neurological diseases are being associated with this deficiency (Molero-Luis et al.2015). There is evidence that metabolism of the transmitter DA by the enzyme monoamine oxidase contributes to striatal damage in mitochondrial toxin-induced models of Huntington's disease (Smith et al.2005). This disease is a devastating neurodegenerative disorder that reflects neuronal dysfunction, which can lead to neuronal death in selected brain regions, principally the striatum and cerebral cortex (Browne and Beal 2006). Even the results of the present study shows that FA administration has no effect over DA levels in striatum, cortex and cerebellum/medulla oblongata of animals that received 3NPA, the increment of 5-HIAA levels in striatum of rats treated with FA alone or combined with 3NPA supports the idea that FA modulates biogenic amines in the brain and that folates are needed for the synthesis of norepinephrine and serotonin (Fava and Mischoulon 2009). However, important metabolism may modulate beta-amyloid peptide (Aβ) through up-regulation of alpha-secretase in neurological diseases (Kotagal et al.2018).