Myeloperoxidase Deficiency Inhibits Cognitive Decline in the 5XFAD Mouse Model of Alzheimer’s Disease

Volkman, Rotem; Ben‐Zur, Tali; Kahana, A.; Garty, Ben Zion; Offen, Daniel

doi:10.3389/fnins.2019.00990

Cited by 50 publications

(35 citation statements)

References 57 publications

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“…Previous studies in [41]. A recent study showed that an MPO-deficient mouse model of AD was protected against cognitive decline [42]. Consistent with the previous results, our study may indicate an association between neutrophil adherence and degranulation with executive decline in AD [43,44].…”

Section: Discussionsupporting

confidence: 92%

A peripheral neutrophil-related inflammatory factor predicts a decline in executive function in mild Alzheimer’s disease

Bawa

Krance

Herrmann

et al. 2020

J Neuroinflammation

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Background: Studies suggest a role of the innate immune system, including the activity of neutrophils, in neurodegeneration related to Alzheimer's disease (AD), but prospective cognitive data remain lacking in humans. We aimed to investigate the predictive relationship between neutrophil-associated inflammatory proteins in peripheral blood and changes in memory and executive function over 1 year in patients with AD. Methods: Participants with AD were identified from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Neutrophil gelatinase-associated lipocalin (NGAL), myeloperoxidase (MPO), interleukin-8 (IL-8), macrophage inflammatory protein-1 beta (MIP-1β), and tumor necrosis factor (TNF) were assayed by luminex immunofluorescence multiplex assay at baseline. Confirmatory factor analysis was used to test an underlying neutrophil associated plasma inflammatory factor. Composite z-scores for memory and executive function were generated from multiple tests at baseline and at 1 year. A multiple linear regression model was used to investigate the association of the baseline inflammatory factor with changes in memory and executive function over 1 year. Results: Among AD patients (n = 109, age = 74.8 ± 8.1, 42% women, Mini Mental State Examination [MMSE] = 23.6 ± 1.9), the neutrophil-related inflammatory proteins NGAL (λ = 0.595, p < .001), MPO (λ = 0.575, p < .001), IL-8 (λ = 0.525, p < .001), MIP-1β (λ = 0.411, p = .008), and TNF (λ = 0.475, p < .001) were found to inform an underlying factor. Over 1 year, this inflammatory factor predicted a decline in executive function (β = − 0.152, p = 0.015) but not memory (β = 0.030, p = 0.577) in models controlling for demographics, brain atrophy, white matter hyperintensities, the ApoE ε4 allele, concomitant medications, and baseline cognitive performance.

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Section: Discussionsupporting

confidence: 92%

A peripheral neutrophil-related inflammatory factor predicts a decline in executive function in mild Alzheimer’s disease

Bawa

Krance

Herrmann

et al. 2020

J Neuroinflammation

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“…The facts of cognitive improvement by suppressing MPO activity in AD model mice considered together [ 19 , 20 ], reasonable speculation could be that in the progression of AD, neutrophils adhere to neurovascular walls to release MPO, and MPO produces HClO radicals to generate neuroinflammation. In our previous studies, carnosine supplementation recovered the blood-vessel abnormality in these mice [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

“…Animal model studies have also provided evidence that MPO is involved in the development of AD. It has also been reported that MPO activity inhibition improves cognitive functions in the AD model mice [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Anserine, HClO-scavenger, protected against cognitive decline in individuals with mild cognitive impairment

Masuoka

Lei

et al. 2021

Aging

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Neuroinflammation has been recognized as a promising target when considering strategies for treating AD. In particular, it has been shown that neutrophils and MPO-mediated neuroinflammatory responses with the production of HClO play a role in the progression of AD. In this study, we aimed to evaluate the effects of anserine, a scavenger of HClO, on the protection of cognitive declines in persons with MCI. Fifty-eight elderly volunteers were screened, and 36 MCI individuals were assigned either to an active arm, who received 500 mg anserine per day, or a placebo arm, for 12-weeks. To assess cognitive function, we performed MMSE at baseline and after the ingestion. The data of the MMSE for 30 subjects who completed the follow-up tests were analyzed. A significant difference was detected in the change score of MMSE between the active arm (1.9 ± 2.0; n = 15) and the placebo arm (0 ± 2.8; n = 15) ( p = 0.036). After the correction with the daily intake of anserine, the significance was elevated ( p = 0.0176). Our results suggest that anserine protects elderly persons with MCI from cognitive declines by suppressing MPO-mediated neuroinflammatory responses.

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“…Forced alternation Y-maze was performed to assess spatial memory, as previously described [81,82]. The test was conducted in a white, Perspex Y-shape apparatus with arm length of 38 cm, width of 5 cm, and height of 15 cm.…”

Section: Y-mazementioning

confidence: 99%

Caspase-6 Knockout in the 5xFAD Model of Alzheimer’s Disease Reveals Favorable Outcome on Memory and Neurological Hallmarks

Angel

Volkman

Royal

et al. 2020

IJMS

Self Cite

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the most common form of dementia in the elderly. Caspases, a family of cysteine proteases, are major mediators of apoptosis and inflammation. Caspase-6 is considered to be an up-stream modulator of AD pathogenesis as active caspase-6 is abundant in neuropil threads, neuritic plaques, and neurofibrillary tangles of AD brains. In order to further elucidate the role of caspase-6 activity in the pathogenesis of AD, we produced a double transgenic mouse model, combining the 5xFAD mouse model of AD with caspase-6 knock out (C6-KO) mice. Behavioral examinations of 5xFAD/C6-KO double transgenic mice showed improved performance in spatial learning, memory, and anxiety/risk assessment behavior, as compared to 5xFAD mice. Hippocampal mRNA expression analyses showed significantly reduced levels of inflammatory mediator TNF-α, while the anti-inflammatory cytokine IL-10 was increased in 5xFAD/C6-KO mice. A significant reduction in amyloid-β plaques could be observed and immunohistochemistry analyses showed reduced levels of activated microglia and astrocytes in 5xFAD/C6-KO, compared to 5xFAD mice. Together, these results indicate a substantial role for caspase-6 in the pathology of the 5xFAD model of AD and suggest further validation of caspase-6 as a potential therapeutic target for AD. cleavage into smaller subunits that form the active caspase heterodimer [6]. Caspases have been implicated in numerous diseases as their function leads to apoptosis and cell death [7,8]. Elucidating their roles in those diseases has been the subject of many years of research around the world.Caspase-6 belongs to the pro-apoptotic executioner caspase group and is activated by a series of upstream activators, amongst which are caspase-3 and caspase-1 [9,10]. Caspase-6 was shown to mediate several non-apoptotic processes, such as facilitating axonal pruning during development [11,12]. Cleavage by caspase-6 of the mutant huntingtin gene was shown to be a prerequisite for neuronal dysfunction and degeneration, and therefore, exacerbates neurodegeneration in Huntington's disease [8,13]. Caspase-6 activity is associated with AD pathological lesions and is present at the early stages of tangle formation [14]. The pro-apoptotic protein p53 is increased in AD brains and p53 directly up-regulates the transcription of caspase-6 [15], resulting in a significant increase in caspase-6 mRNA in human AD brains. Caspase-6 cleaves the APP at a specific site, creating the toxic small peptide C31, a potent inducer of apoptosis in cultured neuroblastoma cells [4]. Thus, caspase-6 is considered to be an up-stream modulator of AD pathogenesis, and as a result, a viable therapeutic target for the treatment of AD [8].Caspase-6 knock-out (KO) neurons are protected against excitotoxicity, trophic factor deprivation, and myelin induced axonal degeneration [16]. Caspase-6 KO mice were first described by Uribe et al. [16]. Research using these mice showed a reduction in the inflammatory response and...

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Myeloperoxidase Deficiency Inhibits Cognitive Decline in the 5XFAD Mouse Model of Alzheimer’s Disease

Cited by 50 publications

References 57 publications

A peripheral neutrophil-related inflammatory factor predicts a decline in executive function in mild Alzheimer’s disease

A peripheral neutrophil-related inflammatory factor predicts a decline in executive function in mild Alzheimer’s disease

Anserine, HClO-scavenger, protected against cognitive decline in individuals with mild cognitive impairment

Caspase-6 Knockout in the 5xFAD Model of Alzheimer’s Disease Reveals Favorable Outcome on Memory and Neurological Hallmarks

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