Amyloid ?? peptide induces cytochrome c release from isolated mitochondria

Abstract

Amyloid beta peptide (Abeta) is a neurotoxic metabolic product of the amyloid precursor protein (APP). Abeta is strongly implicated in the pathology of Alzheimer's disease (AD) and can be formed intracellularly. In this study, we show that the addition of Abeta to isolated mouse brain mitochondria can directly induce cytochrome c (Cyt c) release and mitochondrial swelling, which were partially inhibited by cyclosporin A (CsA). These results suggest that the Abetaaccumulated intracellularly by APP processing might exert neurotoxicity by interacting with mitochondria and inducing mitochondrial swelling and release of Cyt c, which activates caspase-3 and finally can lead to apoptosis in neuronal cells and to neurodegeneration in AD.

Progressive neuronal loss and behavioral impairments of transgenic C57BL/6 inbred mice expressing the carboxy terminus of amyloid precursor protein

“…In cultured neuronal cells, various forms of CTFs, for examples, CTF31, AICD (CTF57 and CTF59), and hCTF99, can exert neurotoxicity, which is associated with the induction of glycogen synthase kinase 3h or with the inhibition of histone deacetylation (Kim et al, 2003. Furthermore, the carboxyl-terminal fragment of APP with 105 amino acids (CTF105) can disturb Ca 2+ homeostasis in cultured cells (Suh and Checler, 2002) and disrupt mitochondrial function, which leads to increased cytochrome c release and caspase 3 activation (Kim et al, 2002). In addition, CTF104 increases the production of IL-1h, TNFa, and NO in cultured astrocytes (Suh and Checler, 2002).…”

β-Amyloid Peptides Induce Mitochondrial Dysfunction and Oxidative Stress in Astrocytes and Death of Neurons through Activation of NADPH Oxidase

“…Enzyme systems containing iron-sulfur centers, including several enzyme complexes of the respiratory chain, ␣-ketoglutarate dehydrogenase, and aconitase, are particularly vulnerable to damage by both ␤A and ROS (Blass and Gibson, 1991;Casley et al, 2002b;Longo et al, 2000). ␤A also has multiple direct effects on isolated mitochondria, causing alterations in enzyme activity, damage to the respiratory chain, and opening of the mitochondrial permeability transition pore (Canevari et al, 1999;Parks et al, 2001;Shevtzova et al, 2001;Kim et al, 2002;Moreira et al, 2002). The latter may trigger cell death, either promoting cytochrome c release and apoptosis or causing energetic failure and necrosis.…”

Aβ(31–35) and Aβ(25–35) fragments of amyloid beta‐protein induce cellular death through apoptotic signals: Role of the redox state of methionine‐35

“…However, although the deposition of Ab in the central nervous system is a hallmark of AD and a possible cause of neurodegeneration [1,8,9], several reports have suggested that some non-aggregated amyloid molecules and its peptide fragments, may intercalate into the plasma membrane and directly alter membrane activities [10,11]. Recent studies evidenced that at earlier stages of AD, the non-aggregated form of Ab fragments namely Ab (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) mono/oligomer forms are also able to cross the cellular plasmatic membranes inducing intracellular mechanisms of toxicity [12,13]. Previous papers have reported that programmed cell death pathways may be involved in the mechanisms responsible for AD [14,15].…”