Reactive Oxygen Species (ROS) are generated primarily during the biological processes of oxidative phosphorylation in mitochondria and the oxidative burst of activated phagocytes.
AD pathogenesis is understandably very complex, and experts of different fields have contributed to aspects of mechanistic understanding of oxidative stress in the disease.
It's generally agreed that multiple cell types have gone wrong in the aging brain.
Emerging processes such as autophagy and ferroptosis have been added to the list of errant cellular processes at work in AD.
As such it is unlikely for us to attribute singly mitochondrial stress or oxidative bursts (implying a heavy role of activated microglia) to the pathological processes.
In general, certainly superoxide (the primary ROS from mitochondria and inflammed microglia) is expected to be elevated in AD brains in a chronic manner, but superoxide is likely to do all the damage, as its chemistry toward major macromolecules and transient nature are well known.
Other "secondary" ROS/RNS are likely at work, notably peroxynitrite (ONOO-), hypochlorous acid (HOCl), H2O2, even hydroxy radical (*OH). The overproduction of these ensure a cellular environment that is overly oxidizing.
Having said that, cells must also suffer from an inability to sufficiently detoxify and repair themselves. The repair systems include Nrf2-Keap1 and autophagy.
Plus, ER stress should also be taken into serious account, along with impaired autophagy, to understand why protein misfolding prevails in AD.
For expert reviews, see some of these (PDFs):
Respected Essam Fadel Alwan Al-Jumaily,
ROS (primarily OH and NO) as free radicals are generated as a byproduct of oxidative phosphorylation in the electron transport chain during ATP synthesis in the mitochondria.
Free radicals (OH and NO) participate in Fenton reaction to synthesize ONOO- ions, which induce oxidative and well as nitrative stress to the beta-amyloid protein and compromise mitochondrial bio-energetics of hippocampal neurons
in AD.
In general, cysteines in the beta-amyloid (1-42) protein have -SH groups which are oxidized to enhance folding. ROS induce structural and functional degradation by impacting long-range and short range forces of electrostatic attraction and repulsion, hydrogen bonds, ionic bonds, dative bonds, and covalent bonds to impair functionally-significant 3D structures to cause denaturation and aggregation of amyloid (1-42) protein in AD patients (particularly when it is truncated).
Respectfully submitted,
Sushil Sharma, Ph.D; D.M.R.I.T
Academic dean
American International School of Medicine
Georgetown, Guyana, South America
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