scholarly journals Strategic Modification of Gut Microbiota through Oral Bacteriotherapy Influences Hypoxia Inducible Factor-1α: Therapeutic Implication in Alzheimer’s Disease

2021 ◽  
Vol 23 (1) ◽  
pp. 357
Author(s):  
Laura Bonfili ◽  
Chunmei Gong ◽  
Francesca Lombardi ◽  
Maria Grazia Cifone ◽  
Anna Maria Eleuteri
Keyword(s):  
Nitric Oxide ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gut Microbiota ◽  
Hypoxia Inducible Factor ◽  
Blood Oxygenation ◽  
Tau Proteins ◽  
Hypoxia Inducible Factor 1Α ◽  
Beneficial Effects ◽  
Cerebral Blood Oxygenation

Dysbiosis contributes to Alzheimer’s disease (AD) pathogenesis, and oral bacteriotherapy represents a promising preventative and therapeutic opportunity to remodel gut microbiota and to delay AD onset and progression by reducing neuroinflammation and amyloid and tau proteins aggregation. Specifically, SLAB51 multi-strain probiotic formulation positively influences multiple neuro-chemical pathways, but exact links between probiotics oral consumption and cerebral beneficial effects remain a gap of knowledge. Considering that cerebral blood oxygenation is particularly reduced in AD and that the decreased neurovascular function contributes to AD damages, hypoxia conditioning represents an encouraging strategy to cure diseases of the central nervous system. In this work, 8-week-old 3xTg-AD and wild-type mice were chronically supplemented with SLAB51 to evaluate effects on hypoxia-inducible factor-1α (HIF-1α), a key molecule regulating host-microbial crosstalk and a potential target in neurodegenerative pathologies. We report evidence that chronic supplementation with SLAB51 enhanced cerebral expression of HIF-1α and decreased levels of prolyl hydroxylase 2 (PHD2), an oxygen dependent regulator of HIF-1α degradation; moreover, it successfully counteracted the increase of inducible nitric oxide synthase (iNOS) brain expression and nitric oxide plasma levels in AD mice. Altogether, the results demonstrate an additional mechanism through which SLAB51 exerts neuroprotective and anti-inflammatory effects in this model of AD.

scholarly journals Probiotics Fermentation Technology, a Novel Kefir Product, Ameliorates Cognitive Impairment in Streptozotocin-Induced Sporadic Alzheimer’s Disease in Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Nesrine S. El Sayed ◽  
Esraa A. Kandil ◽  
Mamdooh H. Ghoneum
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Gut Microbiota ◽  
Neuronal Degeneration ◽  
Amyloid Plaque ◽  
Dependent Manner ◽  
Insulin Degrading Enzyme ◽  
Beneficial Effects ◽  
Fermentation Technology

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by cognitive impairment. Gut microbiota dysfunction (dysbiosis) is implicated in the pathology of AD and is associated with several detrimental consequences, including neurotransmitter depletion, oxidative stress, inflammation, apoptosis, and insulin resistance, which all contribute to the onset of AD. The objective of this study was to assess the effectiveness of Probiotics Fermentation Technology (PFT), a kefir product, in alleviating AD symptoms via regulation of the gut microbiota using a streptozotocin- (STZ-) induced AD mouse model and to compare its activity with simvastatin, which has been proven to effectively treat AD. Mice received one intracerebroventricular injection of STZ (3 mg/kg). PFT (100, 300, 600 mg/kg) and simvastatin (20 mg/kg) were administered orally for 3 weeks. PFT supplementation mitigated STZ-induced neuronal degeneration in the cortex and hippocampus, restored hippocampal acetylcholine levels, and improved cognition in a dose-dependent manner. These effects were accompanied by reductions in oxidative damage, proinflammatory cytokine expression, apoptosis, and tau hyperphosphorylation. Moreover, PFT hindered amyloid plaque accumulation via the enhancement of insulin-degrading enzyme. These beneficial effects were comparable to those produced by simvastatin. The results suggest that PFT can alleviate AD symptoms by regulating the gut microbiota and by inhibiting AD-related pathological events.

scholarly journals Effect of C-phycocyanin on HDAC3 and miRNA-335 in Alzheimer’s disease

2020 ◽  
Vol 11 (1) ◽  
pp. 161-172
Author(s):  
Zhengyu Li ◽  
Li Gan ◽  
Si Yan ◽  
Yufang Yan ◽  
Wei Huang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Spatial Memory ◽  
Therapeutic Option ◽  
Memory Performance ◽  
Tau Proteins ◽  
Therapeutic Effects ◽  
Epigenetic Factors ◽  
Beneficial Effects ◽  
Ameliorative Effect

AbstractBackground:Amyloid-beta (Aβ) plaque deposits and neurofibrillary tangles containing tau proteins are the key pathognomonic manifestations of Alzheimer’s disease (AD). Lack of holistic drugs for AD has reinvigorated enthusiasm in the natural product-based therapies. In this study, our idea to decipher the beneficial effects of C-phycocyanin (CPC) in the management of AD is buoyed by its multifaceted and holistic therapeutic effects.Methods:We evaluated the effect of CPC treatment on epigenetic factors and inflammatory mediators in a mouse with oligomeric Aβ1-42-induced AD. Besides, the cognitive function was evaluated by the spatial memory performance on a radial arm maze.Results:The results showed cognitive deficit in the mice with AD along with upregulated HDAC3 expression and diminished miRNA-335 and brain-derived neurotrophic factor (BDNF) expressions. In addition, inflammation was provoked (manifested by increased interleukins (IL)-6 and IL-1β) and neuronal apoptosis was accelerated (indicated by increased Bax, caspase-3, and caspase-9 along with decreased Bcl2) in the hippocampus of the mice with AD. Interestingly, CPC treatment in the mice with AD improved spatial memory performance and decreased the perturbations in the epigenetic and inflammatory biofactors.Conclusion:These results underscore that mitigation of inflammation via regulation of epigenetic factors might be the key pathway underlying the ameliorative effect of CPC against the aberrations in AD. Our findings provide the rationale for considering CPC as a viable therapeutic option in the management of AD.

Role of Hypoxia Inducible Factor-1α in Alzheimer’s Disease

2021 ◽  
Vol 80 (3) ◽  
pp. 949-961
Author(s):  
Yang-Yang Wang ◽  
Zhen-Ting Huang ◽  
Ming-Hao Yuan ◽  
Feng Jing ◽  
Ruo-Lan Cai ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Targets ◽  
Hypoxia Inducible Factor ◽  
Amyloid Β ◽  
Low Oxygen ◽  
Hypoxia Inducible Factor 1Α ◽  
Hyperphosphorylated Tau Protein ◽  
The One ◽  
Aβ Generation

Amyloid-β (Aβ) peptides and hyperphosphorylated tau protein are the most important pathological markers of Alzheimer’s disease (AD). Neuroinflammation and oxidative stress are also involved in the development and pathological mechanism of AD. Hypoxia inducible factor-1α (HIF-1α) is a transcriptional factor responsible for cellular and tissue adaption to low oxygen tension. Emerging evidence has revealed HIF-1α as a potential medicinal target for neurodegenerative diseases. On the one hand, HIF-1α increases AβPP processing and Aβ generation by promoting β/γ-secretases and suppressing α-secretases, inactivates microglia and reduces their activity, contributes to microglia death and neuroinflammation, which promotes AD pathogenesis. On the other hand, HIF-1α could resist the toxic effect of Aβ, inhibits tau hyperphosphorylation and promotes microglial activation. In summary, this review focuses on the potential complex roles and the future perspectives of HIF-1α in AD, in order to provide references for seeking new drug targets and treatment methods for AD.

scholarly journals The Beneficial Effects of Combining Anti-Aβ Antibody NP106 and Curcumin Analog TML-6 on the Treatment of Alzheimer’s Disease in APP/PS1 Mice

2022 ◽  
Vol 23 (1) ◽  
pp. 556
Author(s):  
Ih-Jen Su ◽  
Chia-Yu Hsu ◽  
Santai Shen ◽  
Po-Kuan Chao ◽  
John Tsu-An Hsu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gut Microbiota ◽  
Combination Treatment ◽  
Curcumin Analog ◽  
Behavioral Deficit ◽  
Beneficial Effects ◽  
Single Target ◽  
Superior Effect ◽  
Treatment Paradigm

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with a multifactorial etiology. A multitarget treatment that modulates multifaceted biological functions might be more effective than a single-target approach. Here, the therapeutic efficacy of combination treatment using anti-Aβ antibody NP106 and curcumin analog TML-6 versus monotherapy was investigated in an APP/PS1 mouse model of AD. Our data demonstrate that both combination treatment and monotherapy attenuated brain Aβ and improved the nesting behavioral deficit to varying degrees. Importantly, the combination treatment group had the lowest Aβ levels, and insoluble forms of Aβ were reduced most effectively. The nesting performance of APP/PS1 mice receiving combination treatment was better than that of other APP/PS1 groups. Further findings indicate that enhanced microglial Aβ phagocytosis and lower levels of proinflammatory cytokines were concurrent with the aforementioned effects of NP106 in combination with TML-6. Intriguingly, combination treatment also normalized the gut microbiota of APP/PS1 mice to levels resembling the wild-type control. Taken together, combination treatment outperformed NP106 or TML-6 monotherapy in ameliorating Aβ pathology and the nesting behavioral deficit in APP/PS1 mice. The superior effect might result from a more potent modulation of microglial function, cerebral inflammation, and the gut microbiota. This innovative treatment paradigm confers a new avenue to develop more efficacious AD treatments.

scholarly journals Gut Microbiota and Dysbiosis in Alzheimer’s Disease: Implications for Pathogenesis and Treatment

2020 ◽  
Vol 57 (12) ◽  
pp. 5026-5043 ◽  
Author(s):  
Shan Liu ◽  
Jiguo Gao ◽  
Mingqin Zhu ◽  
Kangding Liu ◽  
Hong-Liang Zhang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gut Microbiota ◽  
Gut Dysbiosis ◽  
Bidirectional Communication ◽  
Significant Research ◽  
Novel Therapeutic Strategies ◽  
The Brain ◽  
Brain Homeostasis ◽  
Gut Microbiota Composition

Abstract Understanding how gut flora influences gut-brain communications has been the subject of significant research over the past decade. The broadening of the term “microbiota-gut-brain axis” from “gut-brain axis” underscores a bidirectional communication system between the gut and the brain. The microbiota-gut-brain axis involves metabolic, endocrine, neural, and immune pathways which are crucial for the maintenance of brain homeostasis. Alterations in the composition of gut microbiota are associated with multiple neuropsychiatric disorders. Although a causal relationship between gut dysbiosis and neural dysfunction remains elusive, emerging evidence indicates that gut dysbiosis may promote amyloid-beta aggregation, neuroinflammation, oxidative stress, and insulin resistance in the pathogenesis of Alzheimer’s disease (AD). Illustration of the mechanisms underlying the regulation by gut microbiota may pave the way for developing novel therapeutic strategies for AD. In this narrative review, we provide an overview of gut microbiota and their dysregulation in the pathogenesis of AD. Novel insights into the modification of gut microbiota composition as a preventive or therapeutic approach for AD are highlighted.

scholarly journals Crosstalk between Gut and Brain in Alzheimer’s Disease: The Role of Gut Microbiota Modulation Strategies

Nutrients ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 690
Author(s):  
Umair Shabbir ◽  
Muhammad Sajid Arshad ◽  
Aysha Sameen ◽  
Deog-Hwan Oh
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gut Microbiota ◽  
Dietary Habits ◽  
Inflammatory Responses ◽  
Fecal Microbiota Transplantation ◽  
Fecal Microbiota ◽  
Gut Dysbiosis ◽  
Dynamic Population

The gut microbiota (GM) represents a diverse and dynamic population of microorganisms and about 100 trillion symbiotic microbial cells that dwell in the gastrointestinal tract. Studies suggest that the GM can influence the health of the host, and several factors can modify the GM composition, such as diet, drug intake, lifestyle, and geographical locations. Gut dysbiosis can affect brain immune homeostasis through the microbiota–gut–brain axis and can play a key role in the pathogenesis of neurodegenerative diseases, including dementia and Alzheimer’s disease (AD). The relationship between gut dysbiosis and AD is still elusive, but emerging evidence suggests that it can enhance the secretion of lipopolysaccharides and amyloids that may disturb intestinal permeability and the blood–brain barrier. In addition, it can promote the hallmarks of AD, such as oxidative stress, neuroinflammation, amyloid-beta formation, insulin resistance, and ultimately the causation of neural death. Poor dietary habits and aging, along with inflammatory responses due to dysbiosis, may contribute to the pathogenesis of AD. Thus, GM modulation through diet, probiotics, or fecal microbiota transplantation could represent potential therapeutics in AD. In this review, we discuss the role of GM dysbiosis in AD and potential therapeutic strategies to modulate GM in AD.

scholarly journals Repetitive Transcranial Magnetic Stimulation in the Treatment of Alzheimer’s Disease and Other Dementias

Healthcare ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 949
Author(s):  
Athina-Maria Aloizou ◽  
Georgia Pateraki ◽  
Konstantinos Anargyros ◽  
Vasileios Siokas ◽  
Christos Bakirtzis ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transcranial Magnetic Stimulation ◽  
Magnetic Stimulation ◽  
Repetitive Transcranial Magnetic Stimulation ◽  
Lewy Body Dementia ◽  
Standard Of Care ◽  
Central Position ◽  
Beneficial Effects ◽  
Dorsolateral Prefrontal

Dementia is a debilitating impairment of cognitive functions that affects millions of people worldwide. There are several diseases belonging to the dementia spectrum, most prominently Alzheimer’s disease (AD), vascular dementia (VD), Lewy body dementia (LBD) and frontotemporal dementia (FTD). Repetitive transcranial magnetic stimulation (rTMS) is a safe, non-invasive form of brain stimulation that utilizes a magnetic coil to generate an electrical field and induce numerous changes in the brain. It is considered efficacious for the treatment of various neuropsychiatric disorders. In this paper, we review the available studies involving rTMS in the treatment of these dementia types. The majority of studies have involved AD and shown beneficial effects, either as a standalone, or as an add-on to standard-of-care pharmacological treatment and cognitive training. The dorsolateral prefrontal cortex seems to hold a central position in the applied protocols, but several parameters still need to be defined. In addition, rTMS has shown potential in mild cognitive impairment as well. Regarding the remaining dementias, research is still at preliminary phases, and large, randomized studies are currently lacking.

scholarly journals Cytokine signaling convergence regulates the microglial state transition in Alzheimer’s disease

2021 ◽  
Author(s):  
Shun-Fat Lau ◽  
Amy K. Y. Fu ◽  
Nancy Y. Ip
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Signaling Pathways ◽  
State Transition ◽  
Cytokine Signaling ◽  
Interleukin 33 ◽  
Beneficial Effects ◽  
Activated State ◽  
Therapeutic Development ◽  
Functional States

AbstractGenetic analyses have revealed the pivotal contribution of microglial dysfunctions to the pathogenesis of Alzheimer’s disease (AD). Along AD progression, the accumulation of danger-associated molecular patterns (DAMPs) including beta-amyloid and hyperphosphorylated tau continuously stimulates microglia, which results in their chronic activation. Chronically activated microglia secrete excessive pro-inflammatory cytokines, which further regulate microglial responses towards DAMPs. This has spurred longstanding interest in targeting cytokine-induced microglial responses for AD therapeutic development. However, the cytokine-induced microglial state transition is not comprehensively understood. Cytokines are assumed to induce microglial state transition from a resting state to an activated state. However, recent evidence indicate that this microglial state transition involves multiple sequential functional states. Moreover, the mechanisms by which different functional states within the cytokine-induced microglial state transition regulate AD pathology remain unclear. In this review, we summarize how different cytokine signaling pathways, including those of IL-33 (interleukin-33), NLRP3 inflammasome–IL-1β, IL-10, and IL-12/IL-23, regulate microglial functions in AD. Furthermore, we discuss how the modulation of these cytokine signaling pathways can result in beneficial outcomes in AD. Finally, we describe a stepwise functional state transition of microglia induced by cytokine signaling that can provide insights into the molecular basis of the beneficial effects of cytokine modulation in AD and potentially aid therapeutic development.

scholarly journals Alterations in the Gut-Microbial-Inflammasome-Brain Axis in a Mouse Model of Alzheimer’s Disease

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 779
Author(s):  
Pradeep K. Shukla ◽  
David F. Delotterie ◽  
Jianfeng Xiao ◽  
Joseph F. Pierre ◽  
RadhaKrishna Rao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Gut Microbiota ◽  
Transgenic Mice ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Gut Barrier Function ◽  
Elevated Expression ◽  
5Xfad Mice

Alzheimer’s disease (AD), a progressive neurodegenerative disorder characterized by memory loss and cognitive decline, is a major cause of death and disability among the older population. Despite decades of scientific research, the underlying etiological triggers are unknown. Recent studies suggested that gut microbiota can influence AD progression; however, potential mechanisms linking the gut microbiota with AD pathogenesis remain obscure. In the present study, we provided a potential mechanistic link between dysbiotic gut microbiota and neuroinflammation associated with AD progression. Using a mouse model of AD, we discovered that unfavorable gut microbiota are correlated with abnormally elevated expression of gut NLRP3 and lead to peripheral inflammasome activation, which in turn exacerbates AD-associated neuroinflammation. To this end, we observe significantly altered gut microbiota compositions in young and old 5xFAD mice compared to age-matched non-transgenic mice. Moreover, 5xFAD mice demonstrated compromised gut barrier function as evident from the loss of tight junction and adherens junction proteins compared to non-transgenic mice. Concurrently, we observed increased expression of NLRP3 inflammasome and IL-1β production in the 5xFAD gut. Consistent with our hypothesis, increased gut–microbial–inflammasome activation is positively correlated with enhanced astrogliosis and microglial activation, along with higher expression of NLRP3 inflammasome and IL-1β production in the brains of 5xFAD mice. These data indicate that the elevated expression of gut–microbial–inflammasome components may be an important trigger for subsequent downstream activation of inflammatory and potentially cytotoxic mediators, and gastrointestinal NLRP3 may promote NLRP3 inflammasome-mediated neuroinflammation. Thus, modulation of the gut microbiota may be a potential strategy for the treatment of AD-related neurological disorders in genetically susceptible hosts.

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