Журнал болезни Альцгеймера и паркинсонизма

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Vegetable Oil-derived ‘ Hydroxynonenal ’ Causes Diverse Cell Death Possibly Leading to Alzheimer ’s and Related Lifestyle Diseases

Tetsumori Yamashima, Piyakarn Boontem, Hiroki Shimizu, Tsuguhito Ota, Mitsuru Kikuchi, Tatsuya Yamashita, Eishiro Mizukoshi and Shuichi Kaneko

Objective: The real culprit of Alzheimer’s disease remains unelucidated for more than a century. Since Alzheimer’s disease is often associated with lifestyle diseases such as type 2 diabetes, there should be a common causative factor. To elucidate this, we focused on ‘Hydroxynonenal’ that is generated during deep frying of ω-6 Polyunsaturated Fatty Acids (PUFAs).

Methods: Monkeys after consecutive injections of the synthetic Hydroxynonenal were histologically studied to determine, whether it can induce cell degeneration/death in the brain, liver and pancreas.

Results: In all of the five monkeys injected, hippocampal neurons, hepatocytes and β cells after Hydroxynonenal injections revealed similar microcystic degeneration and scattered cell death by light microscopy. By electron microscopy, degenerating cells generally showed lysosomal permeabilization or rupture, electron-luscent cytoplasm, nuclear dissolution, membrane disruption, mitochondrial injury and accumulation of autophagosomes containing cell debris. The number of vivid lysosomes were remarkably decreased, compared to the controls.

Conclusion: Targeting ‘Hydroxynonenal’ would help elucidate the pathogenesis of not only Alzheimer’s disease but also related lifestyle diseases. Since ω-6 PUFAs can induce both GPR40 activation leading to calpain activation and intrinsic Hydroxynonenal generation leading to Hsp70.1 carbonylation, calpain-mediated cleavage of carbonylated Hsp70.1 was thought to disturb lysosomal membrane integrity to induce programmed cell death.