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 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.

Chronic glucocorticoids consumption triggers and worsens experimental Alzheimer’s disease-like pathology by detrimental immune-modulations

2021 ◽  
Author(s):  
Geoffrey Canet ◽  
Charleine Zussy ◽  
Célia Hernandez ◽  
Nathalie Chevallier ◽  
Nicola Marchi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Deficits ◽  
Functional Outcomes ◽  
Amyloid Β ◽  
Memory Deficits ◽  
Stressful Events ◽  
Main Risk Factor ◽  
Clinical Observations ◽  
The One

Introduction: Among the risk factors identified in the sporadic forms of Alzheimer’s disease (AD), environmental and lifestyle elements are of growing interest. Clinical observations suggest that stressful events can anticipate AD onset, while stress-related disorders can promote AD. Here, we tested the hypothesis that a chronic treatment with glucocorticoids, is sufficient to trigger or exacerbate AD molecular hallmarks. Methods: We first validated a rat model of experimental chronic glucocorticoids consumption (corticosterone in drinking water for 4 weeks). Then, to evaluate the consequences of chronic glucocorticoids consumption on the onset of amyloid-β (Aβ) toxicity, animals chronically treated with glucocorticoids were intracerebroventricularly injected with an oligomeric solution of Aβ25-35 (oAβ) (acute model of AD). We evaluated AD-related cognitive deficits and pathogenic mechanisms, with a special emphasis on neuroinflammatory markers. Results: Chronic corticosterone consumption caused the inhibition of the non-amyloidogenic pathways, the impairment of Aβ clearance processes and the induction of amyloidogenic pathways in the hippocampus. The principal enzymes involved in glucocorticoid receptor (GR) activation and Tau phosphorylation were upregulated. Importantly, the AD-like phenotype triggered by chronic corticosterone was analogous to the one caused by oAβ. These molecular commonalities across models were independent from inflammation, as chronic corticosterone was immunosuppressive while oAβ was pro-inflammatory. When chronic corticosterone consumption anticipated the induction of the oAβ pathology, we found a potentiation of neuroinflammatory processes associated with an exacerbation of synaptic and memory deficits but also an aggravation of AD-related hallmarks. Discussion/Conclusion: This study unravels new functional outcomes identifying chronic corticosterone consumption as a main risk factor for AD and suggests that glucocorticoid-based therapies should be prescribed with caution in populations with AD risk.

scholarly journals Interacting Models of Amyloid-β and Tau Proteins: An Approach to Identify Drug Targets in Alzheimer’s Disease

2021 ◽  
pp. 1-7
Author(s):  
Priya Khadgawat ◽  
J.M. Siddesha ◽  
Dharini Shashank ◽  
Shashanka K. Prasad
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Amyloid Β ◽  
Tau Proteins ◽  
Current Review ◽  
The World ◽  
Associated Proteins ◽  
Made In

Alzheimer’s disease (AD) is the primary cause of dementia affecting millions each year across the world, though still remains incurable. This might be attributed to the lack of knowledge about the associated proteins, their cellular and molecular mechanisms, and the genesis of the disease. The discovery of drugs that earlier revolved around targeting the amyloid-β cascade has now been reformed with the upgraded knowledge of the cross-seeding ability of tau protein which opens new gateways for therapeutic targets. This article provides a comprehensive review of various direct and indirect connecting pathways between the two main proteins involved in development and progression of AD, enabling us to further expand our repertoire of information regarding the etiology of AD. The current review indicates the need for extensive research in this niche, thus considerable advances can be made in understanding AD which eventually helps to improve the current therapeutics against AD.

scholarly journals Alzheimer’s disease as an inflammatory disease

2017 ◽  
Vol 8 (1) ◽  
pp. 37-43 ◽  
Author(s):  
Marta Bolós ◽  
Juan Ramón Perea ◽  
Jesús Avila
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Neuronal Cell Death ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Short Review ◽  
Hyperphosphorylated Tau ◽  
Progressive Dementia ◽  
Hyperphosphorylated Tau Protein

AbstractAlzheimer’s disease (AD) is a neurodegenerative condition characterized by the formation of amyloid-β plaques, aggregated and hyperphosphorylated tau protein, activated microglia and neuronal cell death, ultimately leading to progressive dementia. In this short review, we focus on neuroinflammation in AD. Specifically, we describe the participation of microglia, as well as other factors that may contribute to inflammation, in neurodegeneration.

scholarly journals Looking at Alzheimer’s Disease Pathogenesis from the Nuclear Side

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1261
Author(s):  
Laura D’Andrea ◽  
Ramona Stringhi ◽  
Monica Di Luca ◽  
Elena Marcello
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Neurodegenerative Disorder ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Apoe Ε4 ◽  
Hyperphosphorylated Tau Protein ◽  
Ε4 Allele ◽  
Therapeutic Tools

Alzheimer’s disease (AD) is a neurodegenerative disorder representing the most common form of dementia. It is biologically characterized by the deposition of extracellular amyloid-β (Aβ) senile plaques and intracellular neurofibrillary tangles, constituted by hyperphosphorylated tau protein. The key protein in AD pathogenesis is the amyloid precursor protein (APP), which is cleaved by secretases to produce several metabolites, including Aβ and APP intracellular domain (AICD). The greatest genetic risk factor associated with AD is represented by the Apolipoprotein E ε4 (APOE ε4) allele. Importantly, all of the above-mentioned molecules that are strictly related to AD pathogenesis have also been described as playing roles in the cell nucleus. Accordingly, evidence suggests that nuclear functions are compromised in AD. Furthermore, modulation of transcription maintains cellular homeostasis, and alterations in transcriptomic profiles have been found in neurodegenerative diseases. This report reviews recent advancements in the AD players-mediated gene expression. Aβ, tau, AICD, and APOE ε4 localize in the nucleus and regulate the transcription of several genes, part of which is involved in AD pathogenesis, thus suggesting that targeting nuclear functions might provide new therapeutic tools for the disease.

scholarly journals Drug Development for Alzheimer’s Disease: Microglia Induced Neuroinflammation as a Target?

2019 ◽  
Vol 20 (3) ◽  
pp. 558 ◽  
Author(s):  
Yuan Dong ◽  
Xiaoheng Li ◽  
Jinbo Cheng ◽  
Lin Hou
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Development ◽  
Tau Protein ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Cognitive Changes ◽  
Hyperphosphorylated Tau Protein ◽  
Common Causes ◽  
The Brain

Alzheimer’s disease (AD) is one of the most common causes of dementia. Its pathogenesis is characterized by the aggregation of the amyloid-β (Aβ) protein in senile plaques and the hyperphosphorylated tau protein in neurofibrillary tangles in the brain. Current medications for AD can provide temporary help with the memory symptoms and other cognitive changes of patients, however, they are not able to stop or reverse the progression of AD. New medication discovery and the development of a cure for AD is urgently in need. In this review, we summarized drugs for AD treatments and their recent updates, and discussed the potential of microglia induced neuroinflammation as a target for anti-AD drug development.

scholarly journals The Alzheimer’s disease associated bacterial protease RgpB from P. gingivalis activates the alternative β-secretase meprin β thereby increasing Aβ generation

2019 ◽  
Author(s):  
Fred Armbrust ◽  
Cynthia Colmorgen ◽  
Claus U. Pietrzik ◽  
Christoph Becker-Pauly
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuroblastoma Cells ◽  
Amyloid Β ◽  
Reactive Microglia ◽  
Aβ Peptides ◽  
Bacterial Protease ◽  
Whole Exome ◽  
Aβ Generation ◽  
The Impact

AbstractAlzheimer’s disease (AD) is the most common type of dementia and characterized by tau hyperphosphorylation, oxidative stress, reactive microglia and amyloid-β (Aβ) deposits. A recent study revealed that Porphyromonas gingivalis infection is associated with amyloid β generation in Alzheimer’s disease. Increased Aβ levels, tau degradation and neuronal toxicity were observed as a consequence of ginigipain R (RgpB) activity, a cysteine protease constitutively secreted by P. gingivalis. Of note, we previously identified RgpB as a potent activator of the metalloproteinase meprin β. Interestingly, meprin β is an alternative β-secretase of the amyloid precursor protein (APP), which together with the γ-secretase leads to the generation of aggregation-prone N-terminally truncated Aβ2-x peptides. Importantly, identification of a risk gene variant of meprin β (rs173032) for Alzheimer’s disease using whole-exome sequencing of the BDR cohort further supports the impact of this alternative β-secretase. Thus, we wondered if increased Aβ levels as a consequence of P. gingivalis colonization into the brain might be due to meprin β activation by RgpB. Here, we demonstrate that i) upon incubation with RgpB the proteolytic activity of meprin β at the cell surface of transfected HEK cells or of endogenously expressed enzyme in SH-SY5Y neuroblastoma cells was significantly increased, and that ii) RgpB-mediated increase in meprin β activity leads to massive generation of Aβ-peptides. In conclusion, our findings would further explain the pathogenesis of P. gingivalis in AD brain.

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