Gregory Yeh, Matthe w R Chapman and Weichen Zhou
Alzheimer's disease (AD) is a neurodegenerative disease that is both progressive and fatal. Clinical trials focused on pathogenic hypotheses of extracellular/intracellular protein aggregation caused by oxidative stress or other environmental insults have had setbacks recently. We present a major and serendipitous case of an AD patient in this paper. It's the first time a single patient has been followed for more than 32 years, where the signs of Alzheimer's disease have shown up and gone away many times. In the five episodes of extreme stress, the symptoms of stress resulting in a variety of illnesses, such as memory loss, brain atrophy, high blood pressure, inflammations, decreased immunity, and so on, were found, suggesting that the disease is stress-induced. Seven everyday anti-stress strategies were introduced as part of an anti-stress lifestyle. We discovered a connection between stress/stress hormones and strain/stress hormone impact, as well as the pathways leading to a stress-induced molecular mechanism that explains toxic free radicals (oxidants) and A? and Tau (anti-oxidants). Our mechanism may be extended to other neurodegenerative disorders involving protein stress responses, such as Parkinson's disease and alpha-syncline. Alzheimer's disease is caused by the gradual accumulation of amyloidpeptide (Aβ) and subsequent degeneration of neurons in brain regions involved in learning and memory due to changes in the brain that occur as people age. Two factors that are believed to contribute to neuronal dysfunction and degeneration in AD are increased oxidative stress and increased production of neurotoxic styles of Aβ. Alterations in lipid metabolism might also play roles in AD because the danger of AD is suffering from inheritance of various isoforms of apolipoprotein E, changes in cholesterol metabolism can affect Aβ production in cell culture and in vivo, and medicines that lower cholesterol levels may reduce the danger of AD. However, an immediate link between alterations within the metabolism of cholesterol and other membrane lipids in AD has not been established, and it's not known whether and the way such lipid alterations might result in neuronal dysfunction and death. Membrane microdomains that are rich in cholesterol and sphingolipids play important roles in various cellular signaling pathways. Sphingomyelin may be a major source of ceramides, lipid mediators that are generated when sphingomyelin is cleaved by sphingomyelinases, enzymes activated by inflammatory cytokine, and oxidative stress. Ceramides play important roles in regulating an array of physiological processes, including cell proliferation and differentiation, and a sort of programmed death called apoptosis. In the present study, we document significant increases in levels of membrane-associated oxidative stress, long-chain ceramides, and free cholesterol in brain cells during normal aging in mice, in AD patients, and in neurons exposed to Aβ. The intracellular accumulation of ceramides and cholesterol, and therefore the neurotoxicity of Aβ, will be blocked by α-tocopherol and a smallmolecule inhibitor of ceramide production, suggesting a possible therapeutic good thing about agents that focus on sphingolipid metabolism in AD.
