Impaired hypoxic tolerance and altered protein binding of NADH in presymptomatic APP23 transgenic mice

Büchner, Maren; Huber, Roman; Stürchler-Pierrat, Christine; Staufenbiel, Matthias; Riepe, Matthias W.

doi:10.1016/s0306-4522(02)00280-4

Cited by 19 publications

(10 citation statements)

References 26 publications

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“…Altered proteolytic processing of APP may contribute to impaired energy metabolism, because brain glucose metabolism is decreased in cognition-related brain regions of APP mutant mice in association with increased amounts of Aβ in their brains 21,22 . Moroever, hypoxic tolerance is significantly decreased in presymptomatic APP mutant mice suggesting an early role for perturbed energy metabolism in the pathogenic action of altered APP processing 23 . There is increasing evidence that a systemic abnormality in glucose regulation, and insulin resistance in particular, is a risk factor for AD 24 , although the possible link between diabetes and AD requires further investigation.…”

Section: Cellular Stress: Renegade Radicals and Power Cutsmentioning

confidence: 99%

Pathways towards and away from Alzheimer's disease

Mattson

2004

Nature

2,785

2,058

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Slowly, but surely, Alzheimer's disease (AD) patients lose their memory, their cognitive abilities and even their personalities may change dramatically. These changes are due to the progressive dysfunction and death of nerve cells that are responsible for the storage and processing of information. While drugs can temporarily improve memory, at present there are no treatments that can stop or reverse the inexorable neurodegenerative process. But rapid progress towards understanding the cellular and molecular alterations that are responsible for the neuron's demise is increasing optimism that effective preventative and therapeutic strategies are in the offing.Alzheimer's disease (AD) is a neurodegenerative disorder that currently affects nearly 2% of the population in industrialized countries; the risk of AD dramatically increases in individuals beyond the age of 70 and it is predicted that the incidence of AD will triple within the next 50 years (www.alz.org). There can be other causes of memory loss and definitive diagnosis of AD therefore requires postmortem examination of the brain, which must contain sufficient numbers of "plaques" and "tangles" to qualify as AD 1, 2 . Plaques are extracellular deposits of fibrils and amorphous aggregates of amyloid β-peptide (Aβ); diffuse deposits of Aβ are also present in high amounts. Neurofibrillary tangles are intracellular fibrillar aggregates of the microtubule-associated protein tau which exhibit hyperphosphorylation and oxidative modifications. Plaques and tangles are present mainly in brain regions involved in learning and memory and emotional behaviors such as the entorhinal cortex, hippocampus, basal forebrain and amygdala. Brain regions with plaques typically exhibit reduced numbers of synapses, and neurites associated with the plaques are often damaged, suggesting that Aβ damages synapses and neurites. Neurons that employ glutamate or acetylcholine as neurotransmitters appear to be particularly affected, but neurons that produce serotonin and norepinephrine are also damaged. This review focuses on the molecular and cellular abnormalities that occur in the brain in AD, how they result in synaptic dysfunction and cell death, and how they can be counteracted. Central to the disease is altered proteolytic processing of the amyloid precursor protein (APP) resulting in the production and aggregation of neurotoxic forms of Aβ. Neurons that degenerate in AD exhibit increased oxidative damage, impaired energy metabolism and perturbed cellular calcium homeostasis; Aβ appears to be an important instigator of these abnormalities. Genetic and environmental factors can determine one's risk for and an understanding of these risk factors and how they modify the amyloid cascade is leading to the development of interventions for the prevention and treatment of AD that range from changes in diet and lifestyle, to vaccines and drugs.

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Section: Cellular Stress: Renegade Radicals and Power Cutsmentioning

confidence: 99%

Pathways towards and away from Alzheimer's disease

Mattson

2004

Nature

2,785

2,058

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“…First, brain glucose metabolism is decreased in cognition-related brain regions of βAPP mutant mice in association with increased amounts of Aβ [174]. Second, hypoxic tolerance is significantly decreased in presymptomatic βAPP mutant mice [175]. Third, dietary restriction protects neurons in experimental models relevant to AD [34].…”

Section: Mitochondria and Endoplasmic Reticulum Dysfunctionmentioning

confidence: 99%

Alzheimers Disease-Associated Neurotoxic Mechanisms and Neuroprotective Strategies

Pereira¹,

Agostinho²,

Moreira³

et al. 2005

CDTCNSND

115

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The characteristic hallmarks of Alzheimer's disease (AD), the most common form of dementia in the elderly, include senile plaques, mainly composed of beta-amyloid (Abeta) peptide, neurofibrillary tangles and selective synaptic and neuronal loss in brain regions involved in learning and memory. Genetic studies, together with the demonstration of Abeta neurotoxicity, led to the development of the amyloid cascade hypothesis to explain the AD-associated neurodegenerative process. However, a modified version of this hypothesis has emerged, the Abeta cascade hypothesis, which takes into account the fact that soluble oligomeric forms and protofibrils of Abeta and its intraneuronal accumulation also play a key role in the pathogenesis of the disease. Recent evidence posit that synaptic dysfunction triggered by non fibrillar Abeta species is an early event involved in memory decline in AD. The current understanding of the molecular mechanisms responsible for impaired synaptic function and cognitive deficits is outlined in this review, focusing on oxidative stress and disturbed metal ion homeostasis, Ca(2+) dysregulation, mitochondria and endoplasmic reticulum dysfunction, cholesterol dyshomeostasis and impaired neurotransmission. The activation of apoptotic cell death as a mechanism of neuronal loss in AD, and the prominent role of neuroinflammation in this neurodegenerative disorder, are also reviewed herein. Furthermore, we will focus on the more relevant therapeutical strategies currently used, namely those involving antioxidants, drugs for neurotransmission improvement, hormonal replacement, gamma- and beta- secretase inhibitors, Abeta clearance agents (Abeta immunization, disruption of Abeta fibrils, modulation of the cholesterol-mediated Abeta transport), non-steroidal anti-inflammatory drugs (NSAIDs), microtubules stabilizing drugs and kinase inhibitors.

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“…Recently, there has been considerable attention given to spectrally and time-resolved studies of NADH fluorescence (9)(10)(11)(12). A key advantage of the time resolved method is that the excitedstate lifetime of a fluorophore is independent of its concentration.…”

Section: Introductionmentioning

confidence: 99%

Metabolic Mapping of MCF10A Human Breast Cells via Multiphoton Fluorescence Lifetime Imaging of the Coenzyme NADH

Bird

Long²,

Vrotsos³

et al. 2005

Cancer Research

353

373

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Biochemical estimation of NADH concentration is a useful method for monitoring cellular metabolism, because the NADH/NAD + reduction-oxidation pair is crucial for electron transfer in the mitochondrial electron chain. In this article, we present a novel method for deriving functional maps of intracellular reduction-oxidation ratio in vivo via measurement of the fluorescence lifetimes and the ratio of free and protein-bound NADH using two-photon fluorescence lifetime imaging (FLIM). Through systematic analysis of FLIM data from the control cells, it was observed that there is a statistically significant decrease in the fluorescence lifetime of both free and protein-bound NADH and the contribution of proteinbound NADH as cells progress from an early to logarithmic to confluent phase. Potassium cyanide (KCN) treatment and serum starvation of cells yielded similar changes. There was a statistically significant decrease in the fluorescence lifetime of protein-bound and free NADH at the early and logarithmic phase of the growth curve and a statistically significant decrease in the contribution of protein-bound NADH relative to that observed in the control cells at all three phases of the growth curve. The imposed perturbations (confluence, serum starvation, and KCN treatment) are all expected to result in an increase in the ratio of NADH/NAD + . Our studies suggest that the fluorescence lifetime of both the free and the protein-bound components of NADH and the ratio of free to protein-bound NADH is related to changes in the NADH/NAD + ratio.

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Impaired hypoxic tolerance and altered protein binding of NADH in presymptomatic APP23 transgenic mice

Cited by 19 publications

References 26 publications

Pathways towards and away from Alzheimer's disease

Pathways towards and away from Alzheimer's disease

Alzheimers Disease-Associated Neurotoxic Mechanisms and Neuroprotective Strategies

Metabolic Mapping of MCF10A Human Breast Cells via Multiphoton Fluorescence Lifetime Imaging of the Coenzyme NADH

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