title: Killing Me Softly: Connotations to Unfolded Protein Response and Oxidative Stress in Alzheimer's Disease.
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 bioenergetics, with concomitant generation of oxidative/nitrosative stress. Limited protective mechanisms are inadequate to prevent the free radical-mediated lesions. Finally, neuronal loss is observed in AD-affected brains typically by pathologic apoptosis.
authors.affiliation: Electron Microscopy Platform, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland; Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences (SGGW), Nowoursynowska 159, 02-776 Warsaw, Poland.
authors.forename: Beata
authors.initials: B
authors.lastname: Pająk
authors.affiliation: Electron Microscopy Platform, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland.
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Kania
authors.affiliation: Electron Microscopy Platform, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland; Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences (SGGW), Nowoursynowska 159, 02-776 Warsaw, Poland.
authors.forename: Arkadiusz
authors.initials: A
authors.lastname: Orzechowski
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D006031:Glycosylation; D006706:Homeostasis; D006801:Humans; D008928:Mitochondria / Q000473:pathology*; D009474:Neurons / Q000378:metabolism; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D010766:Phosphorylation; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D056811:Unfolded Protein Response; D016875:tau Proteins
chemical_list: D016564:Amyloid beta-Protein Precursor; D016875:tau Proteins; D010100:Oxygen