Expression of endothelial and inducible NOS-isoforms is increased in Alzheimer’s disease, in APP23 transgenic mice and after experimental brain lesion in rat: evidence for an induction by amyloid pathology

Lüth, Hans-Joachim; Holzer, Max; Gärtner, Ulrich; Staufenbiel, Matthias; Arendt, Thomas

doi:10.1016/s0006-8993(01)02758-5

Cited by 166 publications

(109 citation statements)

References 75 publications

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“…However, its functional role in AD still remains unclear, and this novel interaction with A2M can be used as a starting point for further investigations. In addition, we also detected an interaction between A2M and NOS3, found in close proximity to amyloid plaques (Probst et al 1982), which supports the suggested link between plaque formation and inflammatory processes (Luth et al 2001). However, the most interesting link is between APOE and PSEN1, which had not been reported to date.…”

Section: Direct Interaction Partners Among Ad Seed Proteinssupporting

confidence: 85%

Interactome mapping suggests new mechanistic details underlying Alzheimer's disease

Soler-López¹,

Zanzoni²,

Lluís³

et al. 2010

Genome Res.

109

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Recent advances toward the characterization of Alzheimer's disease (AD) have permitted the identification of a dozen of genetic risk factors, although many more remain undiscovered. In parallel, works in the field of network biology have shown a strong link between protein connectivity and disease. In this manuscript, we demonstrate that AD-related genes are indeed highly interconnected and, based on this observation, we set up an interaction discovery strategy to unveil novel AD causative and susceptibility genes. In total, we report 200 high-confidence protein-protein interactions between eight confirmed AD-related genes and 66 candidates. Of these, 31 are located in chromosomal regions containing susceptibility loci related to the etiology of late-onset AD, and 17 show dysregulated expression patterns in AD patients, which makes them very good candidates for further functional studies. Interestingly, we also identified four novel direct interactions among well-characterized AD causative/susceptibility genes (i.e., APP, A2M, APOE, PSEN1, and PSEN2), which support the suggested link between plaque formation and inflammatory processes and provide insights into the intracellular regulation of APP cleavage. Finally, we contextualize the discovered relationships, integrating them with all the interaction data reported in the literature, building the most complete interactome associated to AD. This general view facilitates the analyses of global properties of the network, such as its functional modularity, and triggers many hypotheses on the molecular mechanisms implicated in AD. For instance, our analyses suggest a putative role for PDCD4 as a neuronal death regulator and ECSIT as a molecular link between oxidative stress, inflammation, and mitochondrial dysfunction in AD.

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Section: Direct Interaction Partners Among Ad Seed Proteinssupporting

confidence: 85%

Interactome mapping suggests new mechanistic details underlying Alzheimer's disease

Soler-López¹,

Zanzoni²,

Lluís³

et al. 2010

Genome Res.

109

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“…Finally, although the functional significance of this heterogeneity remains to be clarified, it may have relevance at sites of neuroinflammation where NO contributes to neuropathology, including cerebrovascular dysfunction (Boveri et al 2006;Mark et al 2004;Mayhan 1998) and neurodegeneration (Hewett et al 1994;. In any case, the results reported herein from cultures of astrocytes may explain, at least in part, the apparent heterogeneous expression of NOS-2 in astrocytes in vivo under neuroinflammatory conditions (Iravani et al 2005;Luth et al 2001;Oleszak et al 1998). A. TNFα concentration response.…”

Section: Discussionmentioning

confidence: 80%

TGFβ1 and TNFα potentiate nitric oxide production in astrocyte cultures by recruiting distinct subpopulations of cells to express NOS-2

Hamby¹,

Gragnolati²,

Hewett³

et al. 2008

Neurochemistry International

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Nitric oxide (NO) synthase-2 (NOS-2), a key source of NO at sites of neuroinflammation, is induced in astrocyte cultures treated with lipopolysaccharide (LPS) plus interferon-γ (IFNγ). A recent study examining the regulation of astrocytic NOS-2 expression demonstrated that transforming growth factor-β1 (TGFβ1) potentiated LPS plus IFNγ-induced NOS-2 expression via expansion of the pool of astrocytes that express NOS-2. Results in the current report indicate that this population-based mechanism of increasing NOS-2 expression is not restricted to TGFβ1, since it also accounts for the potentiation of NO production in astrocyte cultures by tumor necrosis factor-α (TNFα). In contrast to TGFβ1, which required 24 hr preincubation for optimal potentiation of NO production, TNFα was maximally effective when added concurrently with LPS plus IFNγ. Nevertheless, under conditions that optimally potentiated NO production, both cytokines recruited similar numbers of astrocytes to express NOS-2 (% NOS-2-positive cells after LPS plus IFNγ alone or with TNFα or TGFβ1 was 9.5 ± 1.2, 25.3 ± 2.9, and 32.4 ± 3.0, respectively). Interestingly, stimulation of astrocytes in the presence of both TGFβ1 and TNFα additively increased the number of astrocytes that expressed NOS-2 protein (% NOS-2-positive cells was 61.0 ± 4.2) relative to each cytokine alone. Potentiation of NO production by either TNFα or TGFβ1 was not ablated by neutralizing antibodies to TGFβ1 or TNFα, respectively. Thus, the two cytokines act independently to recruit separate pools of astrocytes to express NOS-2. These results are consistent with the notion that astrocytes possess an innate heterogeneity with respect to responsiveness to these cytokines. KeywordsLPS; cytokines; heterogeneity; NO; iNOS; nitric oxide synthase Nitric oxide (NO) is an endogenously derived free radical gas that affects a spectrum of homeostatic and physiologic processes, including blood flow and coagulation, normal brain and heart function, and innate immunity (Belge et al. 2005;Ignarro et al. 1999;MacMicking et al. 1997;Yun et al. 1996). However, it can be harmful under certain pathophysiological conditions. Within the CNS, aberrant NO production has been linked to cerebrovascular dysfunction ( Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NO is derived from L-arginine by the catalytic action of three different NOS isoforms (Stuehr 1999). NOS-1 and -3 are constitutively expressed in neurons and endothelial cells, respectively, and thus were initially termed nNOS and eNOS. In contrast, NOS-2 is not constitutively expressed but can be induced ...

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“…Once formed, peroxynitrite can nitrate tyrosine residues to form nitrotyrosine. Additionally, substantial amounts of ONOO-can be protonated at physiological pH to form peroxynitrous acid, a strong oxidant itself, which in turn can yield the highly reactive OH•, a much more powerful oxidant that will readily react with any biological molecules it meets [51,52].Increased nitrotyrosine is found in astrocytes, blood vessels and the neuronal cytoplasm of the cerebral cortex within regions of neurodegeneration in AD, yet it is undetectable in corresponding control regions [24,59,60]. There is also a significant two-to three-fold increase in the lipid nitration product, 5-nitro-γ-tocopherol, in affected regions of the brain in AD, suggesting NO is a significant contributor to lipid oxidation [61].…”

mentioning

confidence: 99%

“…There is also a significant two-to three-fold increase in the lipid nitration product, 5-nitro-γ-tocopherol, in affected regions of the brain in AD, suggesting NO is a significant contributor to lipid oxidation [61]. The widespread occurrence of nitrotyrosine immunoreactivity [24,59,60] suggests that chronic oxidative damage is not restricted to long-lived polymers such as NFTs, but instead, reflects a generalized oxidative stress contributing to the pathogenesis of AD. Consistent with these observations, aberrant expression of all isoforms of NOS and some related proteins is observed in AD.…”

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confidence: 99%

Vascular oxidative stress in Alzheimer disease

Zhu

Smith

Honda

et al. 2007

Journal of the Neurological Sciences

159

156

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Alzheimer disease and cerebrovascular dementia are two common causes of dementia and, by present diagnostic criteria, are mutually exclusive using vascular pathology as an arbitrary demarcation in differential diagnosis. However, evidence from epidemiological, neuropathological, clinical, pharmacological, and functional studies suggest considerable overlap in risk factors and pathological changes suggesting shared common pathogenic mechanisms between these two diseases such that vascular factors play a vital role in the pathogenesis of Alzheimer disease. A high energy demand and lack of an endogenous fuel reserve make the brain highly dependent upon a continuous blood supply where disruption of cerebral blood vessels and blood flow can have serious consequences on neural activities. Indeed, many studies implicate metabolic defects in Alzheimer disease, such a reduced brain metabolism is one of the best documented abnormalities in the disease. Notably, since endothelial reactive oxygen species such as nitric oxide act as vasodilators at low concentrations, increased production coupled with elevated reactive oxygen species scavenging of nitric oxide, can lead to reduced bioavailability of nitric oxide and increased oxidative stress that damage sensitive vascular cells. In this respect, we and others have demonstrated that oxidative stress is one of the earliest pathological changes in the brain of Alzheimer disease patients and plays a critical role in the vascular abnormalities underlying metabolic defects in Alzheimer disease. Here, we discuss vascular factors in relation to Alzheimer disease and review hypoperfusion as a potential cause by triggering mitochondrial dysfunction and increased oxidative stress initiating the pathogenic process. KeywordsAlzheimer disease; hypoperfusion; mitochondria; nitric oxide; nitric oxide synthase; oxidative stress; vascular abnormalitiesCorrespondence to: George Perry, Ph.D., College of Sciences, University of Texas at San Antonio, 6900 North Loop 1604 West, San Antonio, Texas 78249-0661 USA, , george.perry@utsa.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. . Therefore, perivascular Aβ deposits may be a risk factor for reduced regional CBF [7]. Ultrastructural studies on blood vessels associated with Aβ deposits have shown their intermittent association with membrane abnormalities of smooth muscle cells [5]. Indeed, in AD cases with a clinical history of cerebral bleeding, the muscle layer is sometimes completely replaced by Aβ deposits, suggesting that the vascular system may be an initiator for the development of diseas...

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Expression of endothelial and inducible NOS-isoforms is increased in Alzheimer’s disease, in APP23 transgenic mice and after experimental brain lesion in rat: evidence for an induction by amyloid pathology

Cited by 166 publications

References 75 publications

Interactome mapping suggests new mechanistic details underlying Alzheimer's disease

Interactome mapping suggests new mechanistic details underlying Alzheimer's disease

TGFβ1 and TNFα potentiate nitric oxide production in astrocyte cultures by recruiting distinct subpopulations of cells to express NOS-2

Vascular oxidative stress in Alzheimer disease

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