Neurodegenerative Disease Alzheimer’s Disease
APP Swedish double mutation (K670M/N671L) on oxidative-stress- induced cell death mechanisms in PC12 cells. They observed an increased activity of caspase 3 due to an enhanced activation of both intrinsic and extrinsic apoptotic pathways, including activation of the Jun N-terminal kinase (JNK) pathway and an attenuation of apoptosis by SP600125, a JNK inhibitor, through protection against mitochondrial dysfunction and reduction of caspase 9 activity. These results support the idea that the massive neurodegeneration at an early age in familial AD patients could be a result of an increased vulnerability of neurons through the activation of different apoptotic pathways as a consequence of elevated levels of oxidative stress. Yamamori and colleagues47
reported that sub-toxic concentrations (100–500nM) of
Aβ1–42 can downregulate the expression of the X-linked inhibitor of apoptosis (XIAP) in human SH-SY5Y neuroblastoma cells and that
the vulnerability to oxidative stress caused by Aβ1–42 is attenuated by overexpression of XIAP, suggesting that XIAP expression in response
to sub-toxic, more physiological concentrations (100–500nM) of Aβ1–42 increases vulnerability to oxidative stress. Song et al.48
investigated
the possibility that overexpression of Bcl-2 may prevent Aβ-induced cell death through the inhibition of pro-apoptotic activation of p38 mitogen-activated protein kinase (MAPK) and the transcription factor nuclear factor-kappa B (NF-κB) in nerve growth factor (NGF)-induced differentiated PC12 cells. These results suggest that Bcl-2 overexpression protects against Aβ-induced cell death of differentiated PC12 and its protective effect may be related to the reduction of Aβ-induced activation of p38 MAPK and NF-κB.
Tamagno et al.49
used differentiated SK-N-BE neurons to investigate molecular mechanisms and regulatory pathways underlying
apoptotic neuronal cell death elicited by Aβ1–40 and Aβ1–42 peptides as well as the relationship between apoptosis and oxidative stress. They observed that Aβ peptides, used at concentrations able to induce oxidative stress, elicit a classic type of neuronal apoptosis involving mitochondrial regulatory proteins and pathways (i.e. affecting Bax and Bcl-2 protein levels as well as release of cytochrome C in the cytosol), poly-(adeonosine diphosphate [ADP] ribose) polymerase (PARP) cleavage and activation of caspase 3. This pattern of neuronal apoptosis is significantly prevented by α-tocopherol and N-acetyl cysteine and completely abolished by specific inhibitors of stress-activated protein kinases (SAPK) such as JNKs and p38 MAPK, involved in the early increase of p53 protein levels. These results suggest that oxidative-stress-mediated neuronal apoptosis induced by Aβ operates by eliciting a SAPK- dependent regulation of pro-apoptotic mitochondrial pathways involving both p53 and Bcl2.
Animal Studies Anandatheerthavarada et al.50 reported that APP, due to its chimeric
NH2-terminal signal, is targeted to cortical neuronal mitochondria in a Tg mouse model of AD and the accumulation of full-length APP in
the mitochondrial compartment in a membrane-arrested form causes mitochondrial dysfunction and impaired energy metabolism. These results are in accordance with previously discussed in vitro studies and suggest that APP is targeted to neuronal mitochondria under some physiological and pathological conditions. It was also reported that Tg mAPP/ABAD mice display reduced brain levels of ATP and COX activity, diminished glucose utilisation and electrophysiological abnormalities in hippocampal slices compared with Tg mAPP mice.51
By contrast,
neither Tg ABAD mice nor non-transgenic littermates show similar changes in ATP, COX activity, glucose utilisation or electrophysiological
20 properties.51
These findings link ABAD-induced oxidant stress to critical aspects of AD-associated cellular dysfunction, suggesting a pivotal role for this enzyme in the pathogenesis of AD. Previous studies also demonstrated that the mitochondrial abnormalities appear to be key features during the maturation of AD-like pathology in YAC and C57B6/SJL Tg mice. A higher degree of amyloid deposition, overexpression of oxidative stress markers, mtDNA deletion and mitochondrial structural abnormalities in the vascular walls were observed in YAC and C57B6/SJL Tg mice compared with age-matched controls.52,53
Hauptmann and collaborators54 reported that mitochondrial
dysfunction is an early event in mice bearing the human Swedish and London mutations and these mitochondrial defects accumulate with age. Recently, Fu et al.55
mitochondrial abnormalities occurring in PS1 Tg mice. Recently, Takuma et al.56
also reported that ageing potentiates the performed a comparative study using mice
deficient in caspase 3 versus wild-type mice. They microinjected Aβ1–40 into the hippocampal region of the brains of adult mice and found a
significant cellular loss in the hippocampal regions of wild-type mice and a dramatic rescue of neuronal cell death in caspase-3-deficient mice, with gene dosage effect. Furthermore, they observed that Aβ induces a small amount of cell death in cultured neurons prepared from the foetal brain of caspase-3-deficient mice; however, cells from wild-type mice suffer a drastic decrease in cell viability. These results suggest that Aβ-induced neuronal death is mediated by caspase 3 apoptotic cascade. Kaminsky and Kosenko57
investigated the in vivo
effects of Aβ peptides on mitochondrial and non-mitochondrial enzymatic sources of ROS and antioxidant enzymes in the rat brain. The authors observed that the continuous intracerebroventricular
infusion of both Aβ25–35 and Aβ1–40 for up to 14 days stimulates H2O2 generation in isolated neocortex mitochondria. Infusion of Aβ1–40 leads to an increase in MnSOD activity and a decrease in activities of catalase
and glutathione peroxidase in mitochondria, leading to an increase in Cu/ZnSOD and aldehyde oxidase activities, and promotes the conversion of xanthine dehydrogenase to xanthine oxidase leading to an increase in the rate of H2O2 formation in the cytosol.57
Resende and
reported that the triple Tg mouse model of AD presents decreased levels of glutathione (GSH) and vitamin E and increased levels of lipid peroxidation. Additionally, the authors observed an increased activity of the antioxidant enzymes GPx and SOD.58
collaborators58 These
alterations are evident during the Aβ oligomerisation period, before the appearance of Aβ plaques and NFTs, supporting the view that oxidative stress occurs early in the development of the disease.
observed that Tg mice overexpressing the P301L mutant human tau protein present alterations of metabolism-related proteins, including mitochondrial respiratory chain complex components, antioxidant enzymes and synaptic proteins that are associated with increased oxidative stress. Furthermore, the authors observed that mitochondria from these Tg mice display increased vulnerability towards Aβ insult, suggesting a synergistic action of tau and Aβ pathology on the mitochondria. The authors suggest that tau pathology involves a mitochondrial and oxidative stress disorder possibly distinct from that caused by Aβ.
David et al.59 Human Studies
It was previously demonstrated that ABAD is a direct molecular link from Aβ to mitochondrial toxicity.60
The authors created a crystal form
composed of ABAD and Aβ that demonstrates that both molecules interact and accumulate inside mitochondria of AD patients as well as
EUROPEAN NEUROLOGICAL REVIEW
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92 |
Page 93 |
Page 94 |
Page 95 |
Page 96 |
Page 97 |
Page 98 |
Page 99 |
Page 100 |
Page 101 |
Page 102 |
Page 103 |
Page 104 |
Page 105 |
Page 106 |
Page 107 |
Page 108 |
Page 109 |
Page 110 |
Page 111 |
Page 112 |
Page 113 |
Page 114 |
Page 115 |
Page 116