By Ralph Sanchez, MTCM, CNS, D.Hom.
New research published Oct. 13 by the journal Neurobiology of Aging revealed that the free radicals produced during oxidative stress bind to a protein receptor in the brain designated as “the Thromboxane Receptor A2 (TP)”. The study, “Modulation of AD Neuropathology and Memory Impairments by the Isoprostane F2α Is Mediated by the Thromboxane Receptor” demonstrated that oxygen free radicals actually bind to TP, and transmit signals to neuronal cells to increase the production of amyloid beta, and Neurofibrillary Tangles (abnormal phosphorylated microtubule-associated protein tau), the two major pathological lesions associated with Alzheimer’s disease. See illustration just below.
Image courtesy of the National Institute on Aging/National Institutes of Health
The journal article, “Modulation of AD Neuropathology and Memory Impairments by the Isoprostane F2α Is Mediated by the Thromboxane Receptor” demonstrated that 8-isoprostane F2α (8-iso-PGF2α), a biomarker of lipid peroxides*, and mediator in oxidative stress related damage, is implicated in signaling mechanisms that are linked to development of Alzheimer’s disease (AD) related tau neuropathology.(1) The evaluation of F2-isoprostanes is considered to be one the most reliable biomarkers to assess the role of oxidative stress** in the pathogenesis of human disease.(2)
The study analyzed the effect of 8-iso-PGF2α, on tau protein. The increased modification (phosphorylation ) of tau protein in brain cells (neurons) results in the hallmark “neurofribillary tangles” associated in Alzheimer’s disease neurodegeneration. For a more in depth overview of amyloid beta, and neurofibrillary tangles, please read my article “Plaques and Tangles in the Alzheimer’s Brain-Which One Is Most To Blame For Alzheimer’s Disease?” @ https://thealzheimerssolution.com/category/plaques-tangles
In mouse models of AD, the researchers introduced free radicals into the brain and noted marked memory deficits, increased neuroinflammation, and tau protein hyperphosphorylation, and activation of signaling pathways associated with neuronal survival (cyclin kinase 5 pathway).
In another group of mice, the researchers added a pharmacological compound that blocks the TP receptor in the brain, and they found there was no manifestation of the cognitive impairment, or the associated pro-inflammatory, and oxidative stress patterns found in the treated mice.
Domenico Praticὸ, professor of pharmacology and microbiology and immunology in Temple’s School of Medicine said. “Using this compound, we were able to completely neutralize the biological consequences of the free radicals in terms of the amyloid beta production and tau phosphorylation (tangles)”.
This research adds an important piece in the understanding of the molecular mechanisms of oxidative stress in pathogenesis of AD. The thromboxane receptor is now known to be a pivotal player in that scenario, and it reveals just how vital the early assessment for biomarkers of inflammation, and oxidative stress might be in the buffering of such cascades, and the potential prevention of AD.
The study was funded through a grant from the Alzheimer’s Art Quilt Initiative.
* Oxidative Stress: Oxidative stress is a physiological condition whereby there is an imbalance between protective antioxidants and oxidative free radicals and other oxidants. The oxidant/antioxidant balance between antioxidants and the free radicals and oxidants that they quench, is a key element in optimizing health and buffering against the aging process, and the degenerative diseases associated with it.
1. Modulation of AD neuropathology and memory impairments by the isoprostane F2α is mediated by the thromboxane receptor
Elisabetta Lauretti, Antonio Di Meco, Jin Chu, Domenico Praticò
Neurobiology of Aging. Available online 13 October 2014
2. Isoprostanes: markers and mediators of oxidative stress
PAOLO MONTUSCHI, PETER J. BARNES, and L. JACKSON ROBERTS II
The FASEB Journal. December 2004. vol. 18 no. 15 1791-1800