Molecular Mechanisms of Neuroinflammation in Aging and Alzheimer’s Disease Progression

Andronie‐Cioara, Felicia Liana; Ardelean, Adriana Ioana; Nistor-Cseppentö, Delia Carmen; Jurcău, Anamaria; Jurcău, Maria Carolina; Pașcalău, Nicoleta; Marcu, Florin

doi:10.3390/ijms24031869

Cited by 66 publications

(41 citation statements)

References 396 publications

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“…AD-activated microglia often produce excessive amounts of inducible nitric oxide synthase (iNOS), leading to increased NO production, oxidative stress, and neuroinflammation . Superoxide dismutase 1 and 2 (SOD-1 and SOD-2, respectively) are antioxidant enzymes that play a vital role in protecting cells from oxidative stress.…”

Section: Resultsmentioning

confidence: 99%

“…7 Neuroinflammation is characterized by oxidative stress and the rise of activated microglia that release neurotoxic compounds and proinflammatory cytokines, which perpetuates the inflammatory state that eventually leads to neuronal damage. 8 This article is licensed under CC-BY-NC-ND 4 Besides the inhibitors of acetylcholinesterase (AChE) and memantine, the current medical treatment for Alzheimer's patients includes antidepressants, anxiolytics, neuroleptics, and anti-inflammatory drugs. 9 The search for simpler treatments is important to alleviate the burden of the present schemes.…”

Section: ■ Introductionmentioning

confidence: 99%

“…In fact, brain microvessels from Alzheimer’s patients produce higher amounts of cytokines, which certainly contributes to neuronal damage . Neuroinflammation is characterized by oxidative stress and the rise of activated microglia that release neurotoxic compounds and proinflammatory cytokines, which perpetuates the inflammatory state that eventually leads to neuronal damage …”

Section: Introductionmentioning

confidence: 99%

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Improvement of Key Molecular Events Linked to Alzheimer’s Disease Pathology Using Postbiotics

Bulacios,

Cataldo,

Naja

et al. 2023

ACS Omega

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In the past 50 years, life expectancy has increased by more than 20 years. One consequence of this increase in longevity is the rise of age-related diseases such as dementia. Alzheimer’s disease (AD) is the most common form of dementia, accounting for 60–70% of cases. AD pathogenesis is not restricted to the neuronal compartment but includes strong interactions with other brain cells, particularly microglia triggering the release of inflammatory mediators, which contribute to disease progression and severity. There is growing evidence revealing the diverse clinical benefits of postbiotics in many prevalent conditions, including neurodegenerative diseases. Here, we tested the ability of bacterial conditioned media (BCM) derived from selected lactic acid bacteria (LAB) strains to regulate core mechanisms relevant to AD pathophysiology in the microglia cell line BV-2. Levilactobacillus brevis CRL 2013, chosen for its efficient production of the neurotransmitter GABA, and Lactobacillus delbrueckii subsp. lactis CRL 581, known for its anti-inflammatory properties, were selected alongside Enterococcus mundtii CRL 35, a LAB strain that can significantly modulate cytokine production. BCM from all 3 strains displayed antioxidant capabilities, reducing oxidative stress triggered by beta-amyloid oligomers (oAβ 1–42 ). Additionally, BCM effectively mitigated the expression of inflammatory cytokines, namely, TNF-α, IL-1β, and IL-6 triggered by oAβ 1–42 . Furthermore, our study identified that BCM from CRL 581 inhibit the activity of acetylcholinesterase (AChE), a crucial enzyme in AD progression, in both human erythrocytes and mouse brain tissues. Notably, the inhibitory effect was mediated by low-molecular-weight components of the BCM. L. delbrueckii subsp. lactis CRL 581 emerged as a favorable candidate for production of postbiotics with potential benefits for AD therapy since it demonstrated potent antioxidant activity, reduction of cytokine expression, and partial AChE inhibition. On the other hand, E. mundtii CRL 35 showed that the antioxidant activity failed to inhibit AChE and caused induction of iNOS expression, rendering it unsuitable as a potential therapeutic for AD. This study unveils the potential benefits of LAB-derived postbiotics for the development of new avenues for therapeutic interventions for AD.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Improvement of Key Molecular Events Linked to Alzheimer’s Disease Pathology Using Postbiotics

Bulacios,

Cataldo,

Naja

et al. 2023

ACS Omega

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“…Neuroinflammation impairs cognitive function and is a key macro-mechanism uniting brain aging and AD [5], both of which are linked with tau pathology. As such, there is an urgent need to identify safe and well-tolerated treatments that target neuroinflammation, both in the context of brain aging and tauopathy [61].…”

Section: Discussionmentioning

confidence: 99%

Nanoligomers targeting NF-κB and NLRP3 reduce neuroinflammation and improve cognitive function with aging and tauopathy

Wahl,

Risen,

Osburn

et al. 2024

Preprint

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Neuroinflammation contributes to impaired cognitive function in brain aging and neurodegenerative disorders like Alzheimer’s disease, which is characterized by the aggregation of pathological tau. One major driver of both age- and tau-associated neuroinflammation is the NF-κB and NLRP3 signaling axis. However, current treatments targeting NF-κB or NLRP3 may have adverse/systemic effects, and most have not been clinically translatable. Here, we tested the efficacy of a novel, nucleic acid therapeutic (Nanoligomer) cocktail specifically targeting both NF-κB and NLRP3 in the brain for reducing neuroinflammation and improving cognitive function in old wildtype mice, and in a mouse model of tauopathy. We found that 4 weeks of NF-κB/NLRP3-targeting Nanoligomer treatment strongly reduced neuro-inflammatory cytokine profiles in the brain and improved cognitive-behavioral function in both old and tauopathy mice. These effects of NF-κB/NLRP3-targeting Nanoligomer treatment were associated with reduced glial cell activation in old wildtype mice, less pathology in tauopathy mice, favorable changes in transcriptome signatures of inflammation (reduced) and neuronal health (increased) in both mouse models, and positive systemic effects. Collectively, our results provide a basis for future translational studies targeting NF-κB/NLRP3 in the brain, perhaps using Nanoligomers, to inhibit neuroinflammation and improve cognitive function with aging and neurodegenerative disease.

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“…It is clinically characterized by cognitive impairment and memory deterioration, which occur in nearly 70% of all AD cases. Furthermore, AD is becoming a major global public health concern owing to its direct and indirect costs and the increasing aging population worldwide [ 1 ]. However, despite the considerable progress in AD research in the past decade, there are no effective treatments available for AD.…”

Section: Introductionmentioning

confidence: 99%

Anti-Alzheimers molecular mechanism of icariin: insights from gut microbiota, metabolomics, and network pharmacology

Liu

Wang

et al. 2023

J Transl Med

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Background Icariin (ICA), an active ingredient extracted from Epimedium species, has shown promising results in the treatment of Alzheimer's disease (AD), although its potential therapeutic mechanism remains largely unknown. This study aimed to investigate the therapeutic effects and the underlying mechanisms of ICA on AD by an integrated analysis of gut microbiota, metabolomics, and network pharmacology (NP). Methods The cognitive impairment of mice was measured using the Morris Water Maze test and the pathological changes were assessed using hematoxylin and eosin staining. 16S rRNA sequencing and multi-metabolomics were performed to analyze the alterations in the gut microbiota and fecal/serum metabolism. Meanwhile, NP was used to determine the putative molecular regulation mechanism of ICA in AD treatment. Results Our results revealed that ICA intervention significantly improved cognitive dysfunction in APP/PS1 mice and typical AD pathologies in the hippocampus of the APP/PS1 mice. Moreover, the gut microbiota analysis showed that ICA administration reversed AD-induced gut microbiota dysbiosis in APP/PS1 mice by elevating the abundance of Akkermansia and reducing the abundance of Alistipe. Furthermore, the metabolomic analysis revealed that ICA reversed the AD-induced metabolic disorder via regulating the glycerophospholipid and sphingolipid metabolism, and correlation analysis revealed that glycerophospholipid and sphingolipid were closely related to Alistipe and Akkermansia. Moreover, NP indicated that ICA might regulate the sphingolipid signaling pathway via the PRKCA/TNF/TP53/AKT1/RELA/NFKB1 axis for the treatment of AD. Conclusion These findings indicated that ICA may serve as a promising therapeutic approach for AD and that the ICA-mediated protective effects were associated with the amelioration of microbiota disturbance and metabolic disorder. Graphical Abstract

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Molecular Mechanisms of Neuroinflammation in Aging and Alzheimer’s Disease Progression

Cited by 66 publications

References 396 publications

Improvement of Key Molecular Events Linked to Alzheimer’s Disease Pathology Using Postbiotics

Improvement of Key Molecular Events Linked to Alzheimer’s Disease Pathology Using Postbiotics

Nanoligomers targeting NF-κB and NLRP3 reduce neuroinflammation and improve cognitive function with aging and tauopathy

Anti-Alzheimers molecular mechanism of icariin: insights from gut microbiota, metabolomics, and network pharmacology

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