Killing Me Softly: Connotations to Unfolded Protein Response and Oxidative Stress in Alzheimer's Disease

Oxidative Medicine and Cellular Longevity
Beata PająkArkadiusz Orzechowski

Abstract

This review is focused on the possible causes of mitochondrial dysfunction in AD, underlying molecular mechanisms of this malfunction, possible causes and known consequences of APP, Aβ, and hyperphosphorylated tau presence in mitochondria, and the contribution of altered lipid metabolism (nonsterol isoprenoids) to pathological processes leading to increased formation and accumulation of the aforementioned hallmarks of AD. Abnormal protein folding and unfolded protein response seem to be the outcomes of impaired glycosylation due to metabolic disturbances in geranylgeraniol intermediary metabolism. The origin and consecutive fate of APP, Aβ, and tau are emphasized on intracellular trafficking apparently influenced by inaccurate posttranslational modifications. We hypothesize that incorrect intracellular processing of APP determines protein translocation to mitochondria in AD. Similarly, without obvious reasons, the passage of Aβ and tau to mitochondria is observed. APP targeted to mitochondria blocks the activity of protein translocase complex resulting in poor import of proteins central to oxidative phosphorylation. Besides, APP, Aβ, and neurofibrillary tangles of tau directly or indirectly impair mitochondrial biochemistry and...Continue Reading

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Citations

Oct 4, 2016·Molecular Neurobiology·Hao HuJin-Tai Yu
Jun 17, 2020·Expert Opinion on Drug Discovery·Dasol KimHo Jeong Kwon
Jul 5, 2017·The Biochemical Journal·Nisha Grandhi Jayaprakash, Avadhesha Surolia
Aug 19, 2021·Journal of Chemical Neuroanatomy·Yaochen ChuangYouhua Xu

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Methods Mentioned

BETA
GTPase
protein folding
protein
glycosylation
GTPases

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