Nitric Oxide Decreases the Enzymatic Activity of Insulin Degrading Enzyme in APP/PS1 Mice

Kummer, Markus P.; Hülsmann, Claudia; Hermes, Michael; Axt, Daisy; Heneka, Michael T.

doi:10.1007/s11481-011-9339-7

Cited by 24 publications

(19 citation statements)

References 36 publications

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“…NOS2 also favors Aβ elimination by regulating MMP-9/TIMP-1 expression, which is a key enzyme that degrades amyloid (Ridnour et al, 2012). In addition, it has been shown that chronic NO formation may alter insulin-degrading enzyme activity (Kummer et al, 2012). NO synthesis during AD development could also contribute to NFT formation.…”

Section: Molecular Mediators Of Inflammation In Admentioning

confidence: 99%

Inflammatory process in Alzheimer's Disease

Meraz-Ríos¹,

Toral-Ríos²,

Franco-Bocanegra³

et al. 2013

Front. Integr. Neurosci.

318

245

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Alzheimer Disease (AD) is a neurodegenerative disorder and the most common form of dementia. Histopathologically is characterized by the presence of two major hallmarks, the intracellular neurofibrillary tangles (NFTs) and extracellular neuritic plaques (NPs) surrounded by activated astrocytes and microglia. NFTs consist of paired helical filaments of truncated tau protein that is abnormally hyperphosphorylated. The main component in the NP is the amyloid-β peptide (Aβ), a small fragment of 40–42 amino acids with a molecular weight of 4 kD. It has been proposed that the amyloid aggregates and microglia activation are able to favor the neurodegenerative process observed in AD patients. However, the role of inflammation in AD is controversial, because in early stages the inflammation could have a beneficial role in the pathology, since it has been thought that the microglia and astrocytes activated could be involved in Aβ clearance. Nevertheless the chronic activation of the microglia has been related with an increase of Aβ and possibly with tau phosphorylation. Studies in AD brains have shown an upregulation of complement molecules, pro-inflammatory cytokines, acute phase reactants and other inflammatory mediators that could contribute with the neurodegenerative process. Clinical trials and animal models with non-steroidal anti-inflammatory drugs (NSAIDs) indicate that these drugs may decrease the risk of developing AD and apparently reduce Aβ deposition. Finally, further studies are needed to determine whether treatment with anti-inflammatory strategies, may decrease the neurodegenerative process that affects these patients.

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Section: Molecular Mediators Of Inflammation In Admentioning

confidence: 99%

Inflammatory process in Alzheimer's Disease

Meraz-Ríos¹,

Toral-Ríos²,

Franco-Bocanegra³

et al. 2013

Front. Integr. Neurosci.

318

245

View full text Add to dashboard Cite

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“…This data suggests that gal3 is a critical alarmin that amplifies the Aβ-induced proinflammatory response. Since inefficient clearance of Aβ may play a determinant role in AD pathogenesis [76], we analyzed the effect of gal3 in two major mechanisms associated to Aβ clearance: fAβ phagocytosis and IDE-1 levels, a key metalloprotease involved in Aβ degradation by microglia [25,28,39]. Gal3 was able to reduce Aβ phagocytosis, and gal3 deficiency increased IDE-1 levels, suggesting a detrimental role of gal3 in Aβ clearance.…”

Section: Discussionmentioning

confidence: 99%

“…It is believed that sustained proinflammatory molecules such as cytokines, chemokines, nitrogen reactive species (NRS) or reactive oxygen species (ROS) can create a neurotoxic environment driving the progression of AD [1,27,55,63]. Moreover, there is strong evidence supporting the role of inflammatory molecules, such as iNOS, in the initiation of plaque formation due to post-translational modifications of Αβ leading to a faster aggregation [38,39]. Indeed, counteracting the aggregation process has been proposed as a therapeutic strategy to alleviate the progression of the pathology [67].Conclusive evidence supporting a direct role of microglia in human neurodegeneration was revealed with the recent advent of massive genome analysis.…”

mentioning

confidence: 99%

Galectin-3, A Novel Endogenous Trem2 Ligand, Regulates Inflammatory Response and Aβ Fibrilation in Alzheimer’s Disease

Boza-Serrano¹,

Ruiz

Sánchez-Varo³

et al. 2018

Preprint

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Alzheimer's disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (Aβ) peptide, intraneuronal tau neurofibrillary tangles and microglial activation are major pathological hallmarks. One of the key molecules involved in microglial activation is galectin-3 (gal3), and we demonstrate here for the first time a key role of gal3 in AD pathology. Gal3 was highly upregulated in the brains of AD patients and 5xFAD (familial Alzheimer's disease) mice, and found specifically expressed in microglia associated with Aβ plaques. Single nucleotide polymorphisms in the LGALS3 gene, which encodes gal3, were associated to an increased risk of AD. Gal3 deletion in 5xFAD mice attenuated microglia-associated immune responses, particularly those associated with TLR and TREM2/DAP12 signaling. In vitro data demonstrated the requirement of gal3 to fully activate microglia in response to fibrillar Aβ. Gal3 deletion decreased the Aβ burden in 5xFAD mice and improved cognitive behavior. Electron microscopy of gal3 in AD mice demonstrated i) a preferential expression of gal3 by plaque-associated microglia, ii) its presence in the extracellular space and iii) its association to Aβ plaques. Low concentrations (1 nM) of pure gal3 promoted cross-seeding fibrilization of pure Aβ. Importantly, a single intrahippocampal injection of gal3 along with Aβ monomers in WT mice was sufficient to induce the formation of insoluble Aβ aggregates that were absent when gal3 was lacking. High-resolution microscopy (STORM) demonstrated close co-localization of gal3 and TREM2 in microglial processes, and a direct interaction was shown by a fluorescence anisotropy assay involving the gal3 CRD domain. Furthermore, gal3 stimulated the TREM2-DAP12 signaling pathway. In conclusion, we provide evidence that gal3 is a central regulator of microglial immune response in AD. It drives proinflammatory activation and Aβ aggregation, as well as acting as an endogenous ligand to TREM2, a key receptor driving microglial response under disease conditions. Gal3 inhibition may, hence, be a potential pharmacological approach to counteract AD. #Corresponding Authors:Tomas Deierborg (tomas.deierborg@med.lu.se), Jose Luis Venero (jlvenero@us.es) and Antonio Boza-Serrano (antonio.boza_serrano@med.lu.se). Keywords:Alzheimer's disease, Galectin-3, TREM2, Microglial, Amyloid Aggregation. classical hallmarks of AD include the formation of amyloid-beta (Aβ) plaque deposits and of neurofibrillary tangles (NFT) containing abnormal hyperphosphorylation of tau. Over the course of the disease, the deposition of Aβ and the formation of the NFTs appear to be correlated with the on-going hippocampal neurodegeneration [7]. Hippocampal neurodegeneration has a negative effect on the cognitive ability of patients, especially short-term memory, which is impaired. The mechanisms triggering the deposition of the Aβ or the formation of NFT are currently unclear. However, several mechanisms and factors have been suggested to be involved in ...

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“…In AD, activated glial are found clustered around amyloid plaques, and elevated levels of cytokines and other inflammatory mediators found in patients with AD have been proposed to contribute to ongoing pathology, neural dysfunction, and synaptic loss (Mrak and Griffin, 2005;Agostinho et al, 2010;Heneka et al, 2010). More recently, neuroinflammation has also been recognized as a potential part of normal aging (Lucin and Wyss-Coray, 2009;Jurgens and Johnson, 2010). Much research has therefore been aimed at understanding whether inflammatory processes are a causative or contributing factor to pathophysiology and memory loss in AD and cognitive decline that can occur in normal aging.…”

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confidence: 99%

“…Examining one of these mediators, nitric oxide, in an AD model, Kummer et al (2012) report primary in vitro and in vivo data demonstrating that nitric oxide synthesizing enzyme activity negatively regulates amyloid beta degrading enzymes. Montgomery and Bowers (2011) expound the current understanding of TNF alpha function within the CNS under normal physiologic conditions and how it changes with neurodegenerative disorders, particularly multiple sclerosis, AD and Parkinson's disease.…”

mentioning

confidence: 99%