Altered Metabolism of the Amyloid β Precursor Protein Is Associated with Mitochondrial Dysfunction in Down's Syndrome

Busciglio, Jorge; Pelsman, Alejandra; Wong, Caine W.; Pigino, Gustavo; Yuan, Minsheng; Mori, Hiroshi; Yankner, Bruce A.

doi:10.1016/s0896-6273(02)00604-9

Cited by 360 publications

(258 citation statements)

References 67 publications

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“…We recently reported chronic downregulation of mitochondrial activity in DS cells as an adaptive response to minimize oxidative damage and preserve basic cellular functions (Busciglio et al, 2002; Helguera et al, 2013). We further examined mitochondrial function and structure in DS HF and Dp16 MEF.…”

Section: Resultsmentioning

confidence: 99%

“…Oxidative stress in DS has been linked to particular proteins encoded by genes located in Hsa21 that are overexpressed or whose activity is deregulated, namely superoxide dismutase 1 (SOD1), the regulatory kinase Dyrk 1A (DYRK1A), the transcription factor Ets‐2, or the amyloid precursor protein (APP); all of which are directly or indirectly inducers of ROS (Busciglio et al, 2002; Rodríguez‐Sureda et al, 2015; Wolvetang et al, 2003). From a broader perspective, transcriptome studies in DS revealed multiple extra Hsa21 deregulated genes and activated pathways (Bosman et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

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Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells

Zamponi

Coşkun

et al. 2018

Aging Cell

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SummaryMounting evidence implicates chronic oxidative stress as a critical driver of the aging process. Down syndrome (DS) is characterized by a complex phenotype, including early senescence. DS cells display increased levels of reactive oxygen species (ROS) and mitochondrial structural and metabolic dysfunction, which are counterbalanced by sustained Nrf2‐mediated transcription of cellular antioxidant response elements (ARE). Here, we show that caspase 3/PKCδdependent activation of the Nrf2 pathway in DS and Dp16 (a mouse model of DS) cells is necessary to protect against chronic oxidative damage and to preserve cellular functionality. Mitochondria‐targeted catalase (mCAT) significantly reduced oxidative stress, restored mitochondrial structure and function, normalized replicative and wound healing capacity, and rendered the Nrf2‐mediated antioxidant response dispensable. These results highlight the critical role of Nrf2/ARE in the maintenance of DS cell homeostasis and validate mitochondrial‐specific interventions as a key aspect of antioxidant and antiaging therapies.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells

Zamponi

Coşkun

et al. 2018

Aging Cell

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“…Although hypometabolism may simply reflect neuronal loss in the effected regions, mitochondrial dysfunction can be more directly implicated in AD. β-Amyloid undermines mitochondrial stability, inducing both oxidative and bioenergetic crises (Muller et al, 2001;Casley et al, 2002;Canevari et al, 2004), and such mitochondrial impairment in turn enhances the production of Aβ (Busciglio et al, 2002). Similarly, normal distribution of mitochondria in neurons could participate in AD progression secondarily to mitochondrial failure.…”

Section: Mitochondrial Function In Neurodegenerative Diseasesmentioning

confidence: 99%

Estrogen actions on mitochondria—Physiological and pathological implications

Simpkins

Yang

Sarkar

et al. 2008

Molecular and Cellular Endocrinology

134

105

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Estrogens are potent neuroprotective hormones and mitochondria are the site of cellular life-death decisions. As such, it is not surprising that we and other have shown that estrogens have remarkable effects on mitochondrial function. Herein we provide evidence for a primary effect of estrogens on mitochondrial function, achieved in part by the import of estrogen receptor β (ERβ) into the mitochondria where it mediates a number of estrogen actions on this vital organelle. ERβ is imported into the mitochondria, through tethering to cytosolic chaperone protein and/or through direct interaction with mitochondrial import proteins. In the mitochondria, ERβ can affect transcription of critical mitochondrial genes through the interaction with estrogen response elements (ERE) or through protein-protein interactions with mitochondrially imported transcription factors. The potent effects of estrogens on mitochondrial function, particularly during mitochondrial stress, argues for a role of estrogens in the treatment of mitochondrial defects in chronic neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD) and more acute conditions of mitochondrial compromise, like cerebral ischemia and traumatic brain injury.

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“…The granular appearance of intracellular Aβ is also observed in Down syndrome patients with AD (61), indicating that intraneuronal Aβ may be a common feature of AD subtypes. It has been proposed that intraneuronal Aβ accumulation may precede extracellular-plaque pathology in both AD and transgenic mouse models (45,57,(61)(62)(63), further suggesting that caspasecleavage of tau may occur early in AD pathology. However, the notion that intracellular Aβ precedes extracellular-plaque deposition remains controversial.…”

Section: Figurementioning

confidence: 99%

Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology

et al. 2004

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Neurofibrillary tangles (NFTs) are composed of abnormal aggregates of the cytoskeletal protein tau. Together with amyloid β (Aβ) plaques and neuronal and synaptic loss, NFTs constitute the primary pathological hallmarks of Alzheimer disease (AD). Recent evidence also suggests that caspases are activated early in the progression of AD and may play a role in neuronal loss and NFT pathology. Here we demonstrate that tau is cleaved at D421 (ΔTau) by executioner caspases. Following caspase-cleavage, ΔTau facilitates nucleation-dependent filament formation and readily adopts a conformational change recognized by the early pathological tau marker MC1. ΔTau can be phosphorylated by glycogen synthase kinase-3β and subsequently recognized by the NFT antibody PHF-1. In transgenic mice and AD brains, ΔTau associates with both early and late markers of NFTs and is correlated with cognitive decline. Additionally, ΔTau colocalizes with Aβ 1-42 and is induced by Aβ 1-42 in vitro. Collectively, our data imply that Aβ accumulation triggers caspase activation, leading to caspase-cleavage of tau, and that this is an early event that may precede hyperphosphorylation in the evolution of AD tangle pathology. These results suggest that therapeutics aimed at inhibiting tau caspase-cleavage may prove beneficial not only in preventing NFT formation, but also in slowing cognitive decline.

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Altered Metabolism of the Amyloid β Precursor Protein Is Associated with Mitochondrial Dysfunction in Down's Syndrome

Cited by 360 publications

References 67 publications

Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells

Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells

Estrogen actions on mitochondria—Physiological and pathological implications

Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology

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