Mitochondrial mechanisms in amyloid beta peptide-induced cerebrovascular degeneration.
Prevailing evidence suggests that amyloid beta peptide (Abeta), a key mediator in age-dependent neuronal and cerebrovascular degeneration, activates death signaling processes leading to neuronal as well as non-neuronal cell death in the central nervous system. A major cellular event in Abeta-induced death of non-neuronal cells, including cerebral endothelial cells, astrocytes and oligodendrocytes, is mitochondrial dysfunction. The death signaling cascade upstream of mitochondria entails Abeta activation of neutral sphingomyelinase, resulting in the release of ceramide from membrane sphingomyelin. Ceramide then activates protein phosphatase 2A (PP2A), a member in the ceramide-activated protein phosphatase (CAPP) family. PP2A dephosphorylation of Akt and FKHRL1 plays a pivotal role in Abeta-induced Bad translocation to mitochondria and transactivation of Bim. Bad and Bim are pro-apoptotic proteins that cause mitochondrial dysfunction characterized by excessive ROS formation, mitochnondrial DNA (mtDNA) damage, and release of mitochondrial apoptotic proteins including cytochrome c, apoptosis inducing factor (AIF), endonuclease G and Smac. The cellular events activated by Abeta to induce death of non-neuronal cells are complex. Understanding these death signaling processes will aid in the development of more effective strategies to slow down age-dependent cerebrovascular degeneration caused by progressive cerebrovascular Abeta deposition.
Hsu
Ming-Jen
MJ
Graduate Institute of Medical sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Sheu
Joen-Rong
JR
Lin
Chien-Huang
CH
Shen
Ming-Yi
MY
Hsu
Chung Y
CY
D000368:Aged; D000375:Aging / Q000502:physiology*; D016229:Amyloid beta-Peptides / Q000009:adverse effects / Q000502:physiology*; D050197:Atherosclerosis / Q000453:epidemiology / Q000473:pathology; D016923:Cell Death; D002518:Ceramides / Q000378:metabolism; D015140:Dementia, Vascular / Q000453:epidemiology / Q000209:etiology / Q000473:pathology; D006801:Humans; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009410:Nerve Degeneration / Q000473:pathology; D018384:Oxidative Stress; D058225:Plaque, Amyloid / Q000473:pathology; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D020521:Stroke / Q000453:epidemiology / Q000209:etiology*; D014944:World Health Organization
D016229:Amyloid beta-Peptides; D002518:Ceramides; D013108:Sphingomyelin Phosphodiesterase