Neuroinflammatory Cytokines Induce Amyloid Beta Neurotoxicity through Modulating Amyloid Precursor Protein Levels/Metabolism

Alasmari, Fawaz; Alshammari, Musaad A.; Alasmari, Abdullah F.; Alanazi, Wael A.; Alhazzani, Khalid

doi:10.1155/2018/3087475

Cited by 89 publications

(70 citation statements)

References 85 publications

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“…On the other hand, we observe that soluble A 1-42 increases at 6 months, coinciding with the rise in neuroinflammation and the onset of the tauopathy. Previous reports have indicated that inflammatory cytokines can increase -secretase activity in neurons, producing elevated A 1-42 ((Alasmari et al 2018), which is perfectly in line with our model. This supports the use of anti-inflammatory agents at the early stages as a preventive strategy to the proteinopathy as recently reinforced (Hampel et al 2020).…”

Section: Progressive Proteinopathysupporting

confidence: 93%

Systemic Inflammation Causes Microglial Dysfunction with a Mixed AD-Like Pathology.

Bathini

Dupanloup

Zennaro

et al. 2020

Preprint

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Background Alzheimer's disease (AD) is the primary cause of cognitive deficit in elderly humans. Late-onset AD (LOAD) is sporadic, multifactorial, non-Mendelian accounting at present for 95% of the cases in contrast to the genetic form. Risk factors for sporadic AD include Gene: Environment interactions. There is increasing evidence that lifestyle and environmental stress such as infection and chronic inflammation are underlying culprits of neurodegenerative dementia. To date, very few mouse models reproduce the pathophysiological progression of sporadic AD, while the majority of studies have employed transgenic animals reproducing the familial form. Methods We have re-engineered the Polyinosinic:polycytidylic acid (PolyI:C) sterile infection model in wildtype C57Bl6 mice to obtain chronic low-grade systemic inflammation. We have conducted a cross-sectional analysis of aging PolyI:C and Saline control mice (3 months, 6 months, 9 months and 16 months), taking the hippocampus as a reference brain region, based on its vulnerability, and compared the brain aging phenotype to AD progression in humans with mild AD, severe AD and Controls (CTL). Results We found that PolyI:C mice display both peripheral and central inflammation with a peak at 6 months, associated with memory deficits. The hippocampus is characterized by a pronounced and progressive tauopathy. In PolyI:C brains, microglia undergo aging-dependent morphological rearrangements progressively adopting a phagocytic phenotype. Transcriptomic analysis reveals a profound change in gene expression over the course of aging, with a peak in differential expression at 9 months. We confirm that the proinflammatory marker Lcn2 is one of the genes with the strongest upregulation in PolyI:C mice upon aging. Validation in brains from patients with increasing severity of AD shows a general tendency of the genes to decline except for GFAP. Conclusions The PolyI:C model of sterile infection demonstrates that peripheral chronic inflammation is sufficient to cause neuropathological processes resembling a mixed-AD, with progressive tau hyperphosphorylation, changes in microglia morphology, and gene reprogramming reflecting the increased neuroinflammation and the loss of neuronal functionality seen to some extent in humans.

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Section: Progressive Proteinopathysupporting

confidence: 93%

Systemic Inflammation Causes Microglial Dysfunction with a Mixed AD-Like Pathology.

Bathini

Dupanloup

Zennaro

et al. 2020

Preprint

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confidence: 99%

“…Neuroinflammation has been observed as another relevant player in AD pathogenesis in both experimental and clinical studies [11,12,[55][56][57][58][59]. Numerous data demonstrate positive associations between proinflammatory cytokines (e.g., IL-1, IL-6, TNF-α, IL-8, and IL-12) and the progression of AD [58,60]. Moreover, recent investigations reported that these neuroinflammatory cytokines can compromise the clearance of Aβ, accumulating this toxic protein in the brain [57,58,[61][62][63].…”

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confidence: 99%

Oxidative Stress and Dementia in Alzheimer’s Patients: Effects of Synbiotic Supplementation

Ton

Campagnaro

Alves

et al. 2020

Oxidative Medicine and Cellular Longevity

113

115

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Background. Alzheimer’s disease (AD) is the most common cause of dementia in elderly patients. Recently, several studies have shown that inflammation and oxidative stress precede the cardinal neuropathological manifestations of AD. In view of the proven antioxidant effects of probiotics, we proposed that continuous dietary supplementation with milk fermented with kefir grains might improve cognitive and metabolic and/or cellular disorders in the AD patients. Methods. This study was designed as an uncontrolled clinical investigation to test the effects of probiotic-fermented milk supplementation (2 mL/kg/daily) for 90 days in AD patients exhibiting cognitive deficit. Cognitive assessment, cytokine expression, systemic oxidative stress levels, and blood cell damage biomarkers were evaluated before (T0) and after (T90) kefir synbiotic supplementation. Results. When the patients were challenged to solve 8 classical tests, the majority exhibit a marked improvement in memory, visual-spatial/abstraction abilities, and executive/language functions. At the end of the treatment, the cytometric analysis showed an absolute/relative decrease in several cytokine markers of inflammation and oxidative stress markers (⋅O2–, H2O2, and ONOO−, ~30%) accompanied by an increase in NO bioavailability (100%). In agreement with the above findings by using the same technique, we observed in a similar magnitude an improvement of serum protein oxidation, mitochondrial dysfunction, DNA damage/repair, and apoptosis. Conclusion. In conclusion, we demonstrated that kefir improves cognitive deficits, which seems to be linked with three important factors of the AD—systemic inflammation, oxidative stress, and blood cell damage—and may be a promising adjuvant therapy against the AD progression.

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“…In a general sense, the neuroinflammation typical to AD is in part consequence of the accumulation of Aβ [105]. However, inflammation also contributes to the expression of APP [106], and the further aggregation of Aβ [105].…”

Section: Discussionmentioning

confidence: 99%

A Preliminary Study of Cu Exposure Effects upon Alzheimer’s Amyloid Pathology

Pilozzi

Carreras

et al. 2020

Biomolecules

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A large body of evidence indicates that dysregulation of cerebral biometals (Fe, Cu, Zn) and their interactions with amyloid precursor protein (APP) and Aβ amyloid may contribute to the Alzheimer’s disease (AD) Aβ amyloid pathology. However, the molecular underpinnings associated with the interactions are still not fully understood. Herein we have further validated the exacerbation of Aβ oligomerization by Cu and H2O2 in vitro. We have also reported that Cu enhanced APP translations via its 5′ untranslated region (5′UTR) of mRNA in SH-SY5Y cells, and increased Aβ amyloidosis and expression of associated pro-inflammatory cytokines such as MCP-5 in Alzheimer’s APP/PS1 doubly transgenic mice. This preliminary study may further unravel the pathogenic role of Cu in Alzheimer’s Aβ amyloid pathogenesis, warranting further investigation.

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Neuroinflammatory Cytokines Induce Amyloid Beta Neurotoxicity through Modulating Amyloid Precursor Protein Levels/Metabolism

Cited by 89 publications

References 85 publications

Systemic Inflammation Causes Microglial Dysfunction with a Mixed AD-Like Pathology.

Systemic Inflammation Causes Microglial Dysfunction with a Mixed AD-Like Pathology.

Oxidative Stress and Dementia in Alzheimer’s Patients: Effects of Synbiotic Supplementation

A Preliminary Study of Cu Exposure Effects upon Alzheimer’s Amyloid Pathology

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