Lipid Peroxidation And Alzheimer's Disease

stargazer1111

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My original hypothesis that excess vitamin A may be a cause of Alzheimer's has morphed a bit. I now believe that lipid peroxidation is the principal driver and one of the primary problems with excess vitamin A is increased lipid peroxidation.

This paper supports this idea and it means that a diet "deficient" in polyunsaturated fat should prevent Alzheimer's since the only thing that can really peroxidize is polyunsaturated fat. Remove the source of the peroxidation and it doesn't occur.
 

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Beatrix_

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Implication of Vegetable Oil-Derived Hydroxynonenal in the Lysosomal Cell Death for Lifestyle-Related Diseases
Nutrients 2023, 15(3), 609; Implication of Vegetable Oil-Derived Hydroxynonenal in the Lysosomal Cell Death for Lifestyle-Related Diseases

Abstract
Lysosomes are membrane-bound vesicular structures that mediate degradation and recycling of damaged macromolecules and organelles within the cell. For ensuring the place of degradation within the acidic organelle, the integrity of the lysosomal-limiting membrane is critical in order to not injure the cell. As lysosomes fade away in response to acute intense insults or long-term mild insults, dissolving lysosomes are hardly detected during the phase of cell degeneration. If observed at the right time, however, lysosomal membrane rupture/permeabilization can be detected using an electron microscope. In both the experimental and clinical materials, here the author reviewed electron microphotographs showing disintegrity of the lysosomal-limiting membrane. Regardless of insults, cell types, organs, diseases, or species, leakage of lysosomal content occurred either by the apparent disruption of the lysosomal membrane (rupture) and/or through the ultrastructurally blurred membrane (permeabilization). Since lysosomal rupture occurs in the early phase of necrotic cell death, it is difficult to find vivid lysosomes after the cell death or disease are completed. A lipid peroxidation product, 4-hydroxy-2-nonenal (hydroxynonenal), is incorporated into the serum by the intake of ω-6 polyunsaturated fatty acid-rich vegetable oils (exogenous), and/or is generated by the peroxidation of membrane lipids due to the oxidative stress (intrinsic). Exogenous and intrinsic hydroxynonenal may synergically oxidize the representative cell stress protein Hsp70.1, which has dual functions as a ‘chaperone protein’ and ‘lysosomal stabilizer’. Hydroxynonenal-mediated carbonylation of Hsp70.1 facilitates calpain-mediated cleavage to induce lysosomal membrane rupture and the resultant cell death. Currently, vegetable oils such as soybean and canola oils are the most widely consumed cooking oils at home and in restaurants worldwide. Accordingly, high linoleic acid content may be a major health concern, because cells can become damaged by its major end product, hydroxynonenal. By focusing on dynamic changes of the lysosomal membrane integrity at the ultrastructural level, implications of its rupture/permeabilization on cell death/degeneration were discussed as an etiology of lifestyle-related diseases.



Implication of the cooking oil-peroxidation product “hydroxynonenal” for Alzheimer’s disease

Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme that reduces cell injuries via detoxification of lipid-peroxidation product, 4-hydroxy-2-nonenal (hydroxynonenal). It is generated exogenously via deep-frying of linoleic acid-rich cooking oils and/or endogenously via oxidation of fatty acids involved in biomembranes. Although its toxicity for human health is widely accepted, the underlying mechanism long remained unknown. In 1998, Yamashima et al. have formulated the “calpain–cathepsin hypothesis” as a molecular mechanism of ischemic neuronal death. Subsequently, they found that calpain cleaves Hsp70.1 which became vulnerable after the hydroxynonenal-induced carbonylation at the key site Arg469. Since it is the pivotal aberration that induces lysosomal membrane rupture, they suggested that neuronal death in Alzheimer’s disease similarly occurs by chronic ischemia via the calpain–cathepsin cascade triggered by hydroxynonenal. For nearly three decades, amyloid β (Aβ) peptide was thought to be a root substance of Alzheimer’s disease. However, because of both the insignificant correlations between Aβ depositions and occurrence of neuronal death or dementia, and the negative results of anti-Aβ medicines tested so far in the patients with Alzheimer’s disease, the strength of the “amyloid cascade hypothesis” has been weakened. Recent works have suggested that hydroxynonenal is a mediator of programmed cell death not only in the brain, but also in the liver, pancreas, heart, etc. Increment of hydroxynonenal was considered an early event in the development of Alzheimer’s disease. This review aims at suggesting ways out of the tunnel, focusing on the implication of hydroxynonenal in this disease. Herein, the mechanism of Alzheimer neuronal death is discussed by focusing on Hsp70.1 with a dual function as chaperone protein and lysosomal stabilizer. We suggest that Aβ is not a culprit of Alzheimer’s disease, but merely a byproduct of autophagy/lysosomal failure resulting from hydroxynonenal-induced Hsp70.1 disorder. Enhancing ALDH2 activity to detoxify hydroxynonenal emerges as a promising strategy for preventing and treating Alzheimer’s disease.
 

David PS

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This thread deserves more attention. Cooking oil appears to be a major concern. The oil may be 'cooked' in the ships cargo area.

Japan is experiencing an increased incidence of Alzheimer's disease. Tetsumori Yamashima is the lead author of the paper @Beatrix_ cited. In an earlier paper authored by Yamashima he shows that cooking times at 200C increase the amount of hydroxynonenal (HNE) in oils.
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a: HNE generation (ppm) in five representative five cooking oils at 30 and 60 min during 200ºC heating. Extra virgin olive oil generates abundant HNE during heating, because it contains ~10% of linoleic acid. Intriguingly, the product from Australia contained a small amount of HNE prior to heating, because of warm temperature within the ship’s container en route to Japan. Popular can ola oil and rice oil containing abundant linoleic acid generate a large amount of HNE,and both soybean and sunflower oils are similar (data not shown here). In contrast, transfat-free canola oil generates very little, and coconut oil comprising of saturated fatty acids generates negligible HNE.
Possible Prevention of Alzheimer’s Disease by Aldehyde Dehydrogenase:A Perspective Review
 

Beatrix_

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This thread deserves more attention. Cooking oil appears to be a major concern. The oil may be 'cooked' in the ships cargo area.
Apparently there is a connection of increased peroxidation with ALDH2 deficiency. Most research papers analyze it genetically, but I think the deficiency can be caused epigenetically as well.

201607.jpg
 

Beatrix_

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202255.jpg



ALDH2
Aldehyde dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the ALDH2 gene located on chromosome 12.[5][6] ALDH2 belongs to the aldehyde dehydrogenase family of enzymes. Aldehyde dehydrogenase is the second enzyme of the major oxidative pathway of alcohol metabolism. ALDH2 has a low Km for acetaldehyde, and is localized in mitochondrial matrix. The other liver isozyme, ALDH1, localizes to the cytosol.[7]

Most White people have both major isozymes, while approximately 50% of East Asians have the cytosolic isozyme but not a functional mitochondrial isozyme. A remarkably higher frequency of acute alcohol intoxication among East Asians than among Whites could be related to this absence of a catalytically active form of ALDH2. The increased exposure to acetaldehyde in individuals with the catalytically inactive form may also confer greater susceptibility to many types of cancer.[8]
 

Beatrix_

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It appears to be a balanced number of studies finding an association and no association...


Association between ALDH2 Gene Polymorphism and Late-onset Alzheimer Disease: An Up-to-date Meta-analysis
Current Alzheimer Research, Volume 17, Number 2, 2020, pp. 105-111(7)

Abstract
Objectives: Previous case-control studies have focused on the relationship between ALDH2 gene polymorphism and late-onset Alzheimer's Disease (LOAD), but no definite unified conclusion has been reached. Therefore, the correlation between ALDH2 Glu504Lys polymorphism and LOAD remains controversial. To analyze the correlation between ALDH2 polymorphism and the risk of LOAD, we implemented this up-to-date meta-analysis to assess the probable association.

Methods: Studies were searched through China National Knowledge Infrastructure (CNKI), VIP Database for Chinese Technical Periodicals, China Biology Medicine, PubMed, Cochrane Library, Clinical- Trials.gov, Embase, and MEDLINE from January 1, 1994 to December 31, 2018, without any restrictions on language and ethnicity.

Results: Five studies of 1057 LOAD patients and 1136 healthy controls met our criteria for the analysis. Statistically, the ALDH2 GA/AA genotype was not linked with raising LOAD risk (odds ratio (OR) = 1.48, 95% confidence interval (CI) = 0.96-2.28, p = 0.07). In subgroup analysis, the phenomenon that men with ALDH2*2 had higher risk for LOAD (OR = 1.72, 95%CI = 1.10-2.67, p = 0.02) was observed.

Conclusion: This study comprehends only five existing case-control studies and the result is negative. The positive trend might appear when the sample size is enlarged. In the future, more large-scale casecontrol or cohort studies should be done to enhance the association between ALDH2 polymorphism and AD or other neurodegenerative diseases.
 

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