Neuroinflammation and Alzheimer’s disease: lessons learned from 5-lipoxygenase

Joshi, Yash B.; Praticò, Domenico

doi:10.2478/s13380-014-0225-7

Cited by 11 publications

(5 citation statements)

References 44 publications

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“…In contrast to the amyloid cascade hypothesis of AD, which implies that tau pathology is a secondary, downstream phenomenon, the neuropathological findings of Braak and collaborators have fueled a significant controversy concerning the importance or contributions of Aβ burden in producing damage compared to that caused by tau pathology. Additionally, in AD, the pathological Aβ and tau proteins mutually interact and are influenced by many other contributors, such as inflammatory [ 125 ], vascular, and environmental factors, as well as compensatory neuroplastic responses to counteract neural injury associated with neurodegenerative processes [ 126 ], all of which may promote cognitive and behavioral decline.…”

Section: Selective Overview Of Major Discoveries On Tau Protein Anmentioning

confidence: 99%

Tau Protein Hyperphosphorylation and Aggregation in Alzheimer’s Disease and Other Tauopathies, and Possible Neuroprotective Strategies

Šimić

Leko

Wray³

et al. 2016

Biomolecules

533

323

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Abnormal deposition of misprocessed and aggregated proteins is a common final pathway of most neurodegenerative diseases, including Alzheimer’s disease (AD). AD is characterized by the extraneuronal deposition of the amyloid β (Aβ) protein in the form of plaques and the intraneuronal aggregation of the microtubule-associated protein tau in the form of filaments. Based on the biochemically diverse range of pathological tau proteins, a number of approaches have been proposed to develop new potential therapeutics. Here we discuss some of the most promising ones: inhibition of tau phosphorylation, proteolysis and aggregation, promotion of intra- and extracellular tau clearance, and stabilization of microtubules. We also emphasize the need to achieve a full understanding of the biological roles and post-translational modifications of normal tau, as well as the molecular events responsible for selective neuronal vulnerability to tau pathology and its propagation. It is concluded that answering key questions on the relationship between Aβ and tau pathology should lead to a better understanding of the nature of secondary tauopathies, especially AD, and open new therapeutic targets and strategies.

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Section: Selective Overview Of Major Discoveries On Tau Protein Anmentioning

confidence: 99%

Tau Protein Hyperphosphorylation and Aggregation in Alzheimer’s Disease and Other Tauopathies, and Possible Neuroprotective Strategies

Šimić

Leko

Wray³

et al. 2016

Biomolecules

533

323

View full text Add to dashboard Cite

show abstract

“…In contrast to the amyloid cascade hypothesis of AD, which implies that tau pathology is a secondary, downstream phenomenon, the neuropathological findings of Braak and collaborators have fueled a significant controversy concerning the importance or contributions of Aβ burden-induced damage compared to that caused by tau pathology, particularly in LOAD. Additionally, the pathological Aβ and tau proteins mutually interact and are influenced by many other factors, such as epigenetic (Lardenoije et al, 2015), inflammatory (Joshi and Praticò, 2014), vascular, and possibly direct environmental causes (metals, metalloids, pollutants, various compounds in food), as well as compensatory neuroplastic response to counteract neural injury associated with neurodegenerative processes (Wang et al, 2011), all of which may promote cognitive and behavioral decline.…”

Section: Clinical and Neuropathological Criteria For Ad Diagnosismentioning

confidence: 99%

Monoaminergic neuropathology in Alzheimer’s disease

Šimić

Leko

Wray³

et al. 2017

Progress in Neurobiology

234

142

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None of the proposed mechanisms of Alzheimer’s disease (AD) fully explains the distribution patterns of the neuropathological changes at the cellular and regional levels, and their clinical correlates. One aspect of this problem lies in the complex genetic, epigenetic, and environmental landscape of AD: early-onset AD is often familial with autosomal dominant inheritance, while the vast majority of AD cases are late-onset, with the ε4 variant of the gene encoding apolipoprotein E (APOE) known to confer a 5–20 fold increased risk with partial penetrance. Mechanisms by which genetic variants and environmental factors influence the development of AD pathological changes, especially neurofibrillary degeneration, are not yet known. Here we review current knowledge of the involvement of the monoaminergic systems in AD. The changes in the serotonergic, noradrenergic, dopaminergic, histaminergic, and melatonergic systems in AD are briefly described. We also summarize the possibilities for monoamine-based treatment in AD. Besides neuropathologic AD criteria that include the noradrenergic locus coeruleus (LC), special emphasis is given to the serotonergic dorsal raphe nucleus (DRN). Both of these brainstem nuclei are among the first to be affected by tau protein abnormalities in the course of sporadic AD, causing behavioral and cognitive symptoms of variable severity. The possibility that most of the tangle-bearing neurons of the LC and DRN may release amyloid β as well as soluble monomeric or oligomeric tau protein trans-synaptically by their diffuse projections to the cerebral cortex emphasizes their selective vulnerability and warrants further investigations of the monoaminergic systems in AD.

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“…Aside from Aβ, tau and synaptic pathology, activation of microglia and astrocytes is another important feature found consistently in the AD brain, and some work even suggests that these cells play a functional role in AD pathogenesis. 30 Interestingly, in our study we observed that expression levels of CD45 and GFAP, molecular markers of microglia and astyrocytes activation, respectively, were significantly reduced in the group of mice receiving the active drug.…”

Section: Discussionmentioning

confidence: 45%

Pharmacologic blockade of 12/15-lipoxygenase ameliorates memory deficits, Aβ and tau neuropathology in the triple-transgenic mice

Chu

Giannopoulos

et al. 2015

Mol Psychiatry

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The 12/15-lipoxygenase (12/15LO) enzyme is widely distributed within the central nervous system. Previous work showed that this protein is upregulated in Alzheimer's disease (AD), and plays an active role in the development of brain amyloidosis in amyloid beta (Aβ)-precursor protein transgenic mice (Tg2576). In the present paper, we studied the effect of its pharmacologic inhibition on the AD-like phenotype of a mouse model with plaques and tangles, the triple-transgenic mice. Compared with mice receiving placebo, the group treated with PD146176, a specific 12/15LO inhibitor, manifested a significant improvement of their memory deficits. The same animals had a significant reduction in Aβ levels and deposition, which was secondary to a decrease in the β-secretase pathway. In addition, while total tau-soluble levels were unchanged for both groups, PD146176-treated mice had a significant reduction in its phosphorylation state and insoluble fraction, which specifically associated with decrease in stress-activated protein kinase/c-Jun N-terminal kinase activity. In vitro study showed that the effect on tau and Aβ were independent from each other. These data establish a functional role for 12/15LO in the pathogenesis of the full spectrum of the AD-like phenotype and represent the successful completion of the initial step for the preclinical development of 12/15LO inhibitors as novel therapeutic agents for AD.

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Neuroinflammation and Alzheimer’s disease: lessons learned from 5-lipoxygenase

Cited by 11 publications

References 44 publications

Tau Protein Hyperphosphorylation and Aggregation in Alzheimer’s Disease and Other Tauopathies, and Possible Neuroprotective Strategies

Tau Protein Hyperphosphorylation and Aggregation in Alzheimer’s Disease and Other Tauopathies, and Possible Neuroprotective Strategies

Monoaminergic neuropathology in Alzheimer’s disease

Pharmacologic blockade of 12/15-lipoxygenase ameliorates memory deficits, Aβ and tau neuropathology in the triple-transgenic mice

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