Author(s): 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.
