scholarly journals Exploiting the neuroprotective effects of ɑ-klotho to tackle ageing- and neurodegeneration-related cognitive dysfunction

2021 ◽  
Author(s):  
Kelsey Hanson ◽  
Kate Fisher ◽  
Nigel M Hooper
Keyword(s):  
Cognitive Dysfunction ◽  
Significant Proportion ◽  
Amyloid Β ◽  
Synaptic Function ◽  
Ageing Population ◽  
Neuroprotective Effects ◽  
Anti Oxidant ◽  
Klotho Protein ◽  
The Brain

Cognitive dysfunction is a key symptom of aging and neurodegenerative disorders, such as Alzheimer’s disease. Strategies to enhance cognition would impact the quality of life for a significant proportion of the ageing population. The ɑ-klotho protein may protect against cognitive decline through multiple mechanisms: such as promoting optimal synaptic function via activation of N-methyl-D-aspartate receptor signalling; stimulating the anti-oxidant defence system; reducing inflammation; promoting autophagy; and enhancing clearance of amyloid-β. However, the molecular and cellular pathways by which ɑ-klotho mediates these neuroprotective functions have yet to be fully elucidated. Key questions remain unanswered: which form of ɑ-klotho (transmembrane, soluble or secreted) mediates its cognitive enhancing properties; what is the neuronal receptor for ɑ-klotho and which signalling pathways are activated by ɑ-klotho in the brain to enhance cognition; how does peripherally administered ɑ-klotho mediate neuroprotection; and what is the molecular basis for the beneficial effect of the VS variant of ɑ-klotho? In this review we summarise the recent research on neuronal ɑ-klotho and discuss how the neuroprotective properties of ɑ-klotho could be exploited to tackle age- and neurodegeneration-associated cognitive dysfunction.

scholarly journals LongShengZhi Capsule Attenuates Alzheimer-Like Pathology in APP/PS1 Double Transgenic Mice by Reducing Neuronal Oxidative Stress and Inflammation

2020 ◽  
Vol 12 ◽  
Author(s):  
Zequn Yin ◽  
Xuerui Wang ◽  
Shihong Zheng ◽  
Peichang Cao ◽  
Yuanli Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transgenic Mice ◽  
Amyloid Β ◽  
B Cell Lymphoma ◽  
Acanthopanax Senticosus ◽  
Neuroprotective Effects ◽  
Long Term Treatment ◽  
Double Transgenic Mice ◽  
The Brain

Alzheimer’s disease (AD) is the most common form of dementia in the elderly. It may be caused by oxidative stress, inflammation, and cerebrovascular dysfunctions in the brain. LongShengZhi Capsule (LSZ), a traditional Chinese medicine, has been approved by the China Food and Drug Administration for treatment of patients with cardiovascular/cerebrovascular disease. LSZ contains several neuroprotective ingredients, including Hirudo, Astmgali Radix, Carthami Flos (Honghua), Persicae Semen (Taoren), Acori Tatarinowii Rhizoma (Shichangpu), and Acanthopanax Senticosus (Ciwujia). In this study, we aimed to determine the effect of LSZ on the AD process. Double transgenic mice expressing the amyloid-β precursor protein and mutant human presenilin 1 (APP/PS1) to model AD were treated with LSZ for 7 months starting at 2 months of age. LSZ significantly improved the cognition of the mice without adverse effects, indicating its high degree of safety and efficacy after a long-term treatment. LSZ reduced AD biomarker Aβ plaque accumulation by inhibiting β-secretase and γ-secretase gene expression. LSZ also reduced p-Tau expression, cell death, and inflammation in the brain. Consistently, in vitro, LSZ ethanol extract enhanced neuronal viability by reducing L-glutamic acid-induced oxidative stress and inflammation in HT-22 cells. LSZ exerted antioxidative effects by enhancing superoxide dismutase and glutathione peroxidase expression, reduced Aβ accumulation by inhibiting β-secretase and γ-secretase mRNA expression, and decreased p-Tau level by inhibiting NF-κB-mediated inflammation. It also demonstrated neuroprotective effects by regulating the Fas cell surface death receptor/B-cell lymphoma 2/p53 pathway. Taken together, our study demonstrates the antioxidative stress, anti-inflammatory, and neuroprotective effects of LSZ in the AD-like pathological process and suggests it could be a potential medicine for AD treatment.

scholarly journals Isomeric O-methyl cannabidiolquinones with dual BACH1/NRF2 activity

2020 ◽  
Author(s):  
Laura Casares ◽  
Juan Diego Unciti ◽  
Maria Eugenia Prados ◽  
Diego Caprioglio ◽  
Maureen Higgins ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Multiple Sclerosis ◽  
Neurodegenerative Diseases ◽  
Cell Models ◽  
Therapeutic Approaches ◽  
Neuroprotective Effects ◽  
Anti Oxidant ◽  
Anti Inflammatory ◽  
The Brain

ABSTRACTOxidative stress and inflammation in the brain are two key hallmarks of neurodegenerative diseases (NDs) such as Alzheimer’s, Parkinson’s, Huntington’s and multiple sclerosis. The axis NRF2-BACH1 has anti-inflammatory and anti-oxidant properties that could be exploited pharmacologically to obtain neuroprotective effects. Activation of NRF2 or inhibition of BACH1 are, individually, promising therapeutic approaches for NDs. Compounds with dual activity as NRF2 activators and BACH1 inhibitors, could therefore potentially provide a more robust antioxidant and anti-inflammatory effects, with an overall better neuroprotective outcome. The phytocannabinoid cannabidiol (CBD) inhibits BACH1 but lacks significant NRF2 activating properties. Based on this scaffold, we have developed a novel CBD derivative that is highly effective at both inhibiting BACH1 and activating NRF2. This new CBD derivative provides neuroprotection in cell models of relevance to Huntington’s disease, setting the basis for further developments in vivo.

Advanced nanoparticular approaches to combat Alzheimer's disease

2021 ◽  
Vol 09 ◽  
Author(s):  
Rahul Shah ◽  
Sankha Bhattacharya
Keyword(s):  
Alzheimer’S Disease ◽  
Drug Delivery ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Ageing Population ◽  
Disease Therapy ◽  
Cns Penetration ◽  
The Brain ◽  
Improve Patient ◽  
And Oxidative Stress

: Alzheimer's disease (AD) is a neurological disease that affects many of the world's rapidly ageing population. In the etiology of Alzheimer’s disease (AD), the involvement of amyloid β (Aβ) plaque accumulation and oxidative stress in the brain have important roles. Various drugs have been proposed to prevent and treat AD, but delivering these therapeutic agents to the brain is difficult. Over the last decade, nanoparticle-mediated drug delivery represents one promising strategy to increase the CNS penetration of several therapeutic moieties successfully. Different nanocarriers are being investigated to treat and diagnose AD. NTDDS (nanotechnology-based drug delivery systems) can be used in various methods to improve patient compliance and treatment outcomes. However, literature analysis revealed that clinical activities such as NTDDS application in Alzheimer's disease research lag behind despite extensive research. This review gives an account of the BBB and discusses the literature on some drugs which are successfully encapsulated as nanoparticles for a future therapeutic approach. It also emphasizes the current clinical studies for Alzheimer's disease therapy.

scholarly journals Quinacrine directly dissociates amyloid plaques in the brain of 5XFAD transgenic mouse model of Alzheimer’s disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sohui Park ◽  
Hye Yun Kim ◽  
Hyun-A Oh ◽  
Jisu Shin ◽  
In Wook Park ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Weight ◽  
Transgenic Mice ◽  
Cortical Neurons ◽  
Amyloid Β ◽  
Synaptic Function ◽  
Western Blots ◽  
Aβ Fibrils ◽  
The Brain

AbstractAlzheimer’s disease (AD) is the most common type of dementia characterized by the abnormal accumulation of amyloid-β (Aβ) in the brain. Aβ misfolding is associated with neuroinflammation and synaptic dysfunction, leading to learning and memory deficits. Therefore, Aβ production and aggregation have been one of the most popular drug targets for AD. Failures of drug candidates regulating the aforementioned Aβ cascade stimulated development of immunotherapy agents for clearance of accumulated Aβ in the brain. Here, we report that quinacrine, a blood–brain barrier penetrating antimalarial chemical drug, dissociates Aβ plaques in the brain of AD transgenic mice. When co-incubated with pre-formed Aβ fibrils, quinacrine decreased thioflavin T-positive β-sheets in vitro, on top of its inhibitory function on the fibril formation. We confirmed that quinacrine induced dissociation of high-molecular-weight Aβ aggregates into low-molecular-weight species by dot blots in association with size cut-off filtrations. Quinacrine was then administered to adult 5XFAD transgenic mice via weekly intravenous injections for 6 weeks, and we found a significant reduction of Aβ plaques and astrocytosis in their cortex and hippocampus. In western blots of quinacrine-administered mouse brains, amelioration of AD-related biomarkers, glial fibrillary acidic protein, postsynaptic protein 95, phosphorylated cAMP response element-binding protein, phosphorylated c-Jun N-terminal kinase were observed. Lastly, quinacrine-stimulated dissociation of misfolded aggregates induced recovery of synaptic function associated with Aβ in excitatory post-synaptic current recordings of primary rat cortical neurons treated with Aβ aggregates and quinacrine. Collectively, quinacrine can directly dissociate Aβ fibrils and alleviate decreased synaptic functions.

scholarly journals Properties, Pharmacology, and Pharmacokinetics of Active Indole and Oxindole Alkaloids in Uncaria Hook

2021 ◽  
Vol 12 ◽  
Author(s):  
Hirotaka Kushida ◽  
Takashi Matsumoto ◽  
Yasushi Ikarashi
Keyword(s):  
Pharmacological Activity ◽  
Therapeutic Effects ◽  
Neuroprotective Effects ◽  
Drug Products ◽  
Crude Drug ◽  
Future Challenges ◽  
Central Nervous Systems ◽  
Anti Oxidant ◽  
The Brain ◽  
Oxindole Alkaloids

Uncaria Hook (UH) is a dry stem with hook of Ucaria plant and is contained in Traditional Japanese and Chinese medicine such as yokukansan, yokukansankachimpihange, chotosan, Gouteng-Baitouweng, and Tianma-Gouteng Yin. UH contains active indole and oxindole alkaloids and has the therapeutic effects on ailments of the cardiovascular and central nervous systems. The recent advances of analytical technology led to reports of detailed pharmacokinetics of UH alkaloids. These observations of pharmacokinetics are extremely important for understanding the treatment’s pharmacological activity, efficacy, and safety. This review describes properties, pharmacology, and the recently accumulated pharmacokinetic findings of UH alkaloids, and discusses challenges and future prospects. UH contains major indole and oxindole alkaloids such as corynoxeine, isocorynoxeine, rhynchophylline, isorhynchophylline, hirsuteine, hirsutine, and geissoschizine methyl ether (GM). These alkaloids exert neuroprotective effects against Alzheimer’s disease, Parkinson’s disease, and depression, and the mechanisms of these effects include anti-oxidant, anti-inflammatory, and neuromodulatory activities. Among the UH alkaloids, GM exhibits comparatively potent pharmacological activity (e.g., agonist activity at 5-HT1A receptors). UH alkaloids are absorbed into the blood circulation and rapidly eliminated when orally administered. UH alkaloids are predominantly metabolized by Cytochrome P450 (CYP) and converted into various metabolites, including oxidized and demethylated forms. Regarding GM metabolism by CYPs, a gender-dependent difference is observed in rats but not in humans. Several alkaloids are detected in the brain after passing through the blood–brain barrier in rats upon orally administered. GM is uniformly distributed in the brain and binds to various channels and receptors such as the 5-HT receptor. By reviewing the pharmacokinetics of UH alkaloids, challenges were found, such as differences in pharmacokinetics between pure drug and crude drug products administration, food-influenced absorption, metabolite excretion profile, and intestinal tissue metabolism of UH alkaloids. This review will provide readers with a better understanding of the pharmacokinetics of UH alkaloids and their future challenges, and will be helpful for further research on UH alkaloids and crude drug products containing UH.

Active Immunotherapy with 12-mer Aβ1-42-like Assembly Vaccine Shows Efficacy in Aged 3×Tg-AD Mice

2020 ◽  
Vol 20 ◽  
Author(s):  
Hao Fang ◽  
Guo Zhou ◽  
Qingli Li ◽  
Haichao Wang ◽  
Xiaobin Pang ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Senile Plaques ◽  
Synaptic Function ◽  
Synaptic Proteins ◽  
Active Immunotherapy ◽  
T Cell Epitopes ◽  
Neuroprotective Effects ◽  
Aβ Oligomers ◽  
Preclinical Ad ◽  
The Brain

Background: Alzheimer's disease (AD) is the most common progressive neurodegenerative disorder, characterized by senile plaques and neurofibrillary tangles (NFTs). The amyloid-oligomer hypothesis indicates that the buildup of toxic oligomers in vivo is likely to impair memory and synaptic function. Methods: In our study, a kind of novel recombinant chimeric 12×(Aβ1-15-Th) antigen was developed as 12-mer Aβ1-42-like assembly vaccine. We designed this 12×(Aβ1-15-Th) antigen to mimic the assembly states of Aβ1-42 using twelve fold Aβ1–15 (B cell epitopes of human Aβ1-42) and foreign human T helper (Th) epitopes (as the T cell epitopes of Aβ1-42) constructs. Its immunogenicity as a subunit vaccine was tested on C57/BL6 mice, and the efficacy was shown by applying it to AD mice. Results: This 12×(Aβ1-15-Th) vaccine induced robust Aβ-specific antibodies in 3×Tg-AD and C57/BL6 mice. As early immunotherapeutic agent of AD, the 12×(Aβ1-15-Th) vaccine significantly improved the behavior performance of aged 3 × Tg-AD mice, and reduced the levels of soluble Aβ oligomers and soluble Aβ in the brain. In aged 3 × Tg-AD mice, immunotherapy with the 12×(Aβ1-15-Th) vaccine could prevent Aβ-induced decrease of synaptic proteins, which suggested that it has neuroprotective effects on the brain. Conclusion: The novel recombinant 12×(Aβ1-15-Th) chimeric vaccine targeting of pathological conformations of Aβ oligomers has shown obvious neuroprotective benefits in preclinical AD model mouse, which indicates it is a good candidate vaccine for the prophylaxis of AD.

scholarly journals CYP46A1-dependent and independent effects of efavirenz treatment

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Natalia Mast ◽  
Nicole El-Darzi ◽  
Alexey M Petrov ◽  
Young Li ◽  
Irina A Pikuleva
Keyword(s):  
Cytochrome P450 ◽  
Steroid Hormones ◽  
Small Dose ◽  
Amyloid Β ◽  
Enzyme Activation ◽  
Synaptic Function ◽  
Synaptic Density ◽  
5Xfad Mice ◽  
The Brain ◽  
Post Synaptic Density

Abstract Cholesterol excess in the brain is mainly disposed via cholesterol 24-hydroxylation catalysed by cytochrome P450 46A1, a CNS-specific enzyme. Cytochrome P450 46A1 is emerging as a promising therapeutic target for various brain diseases with both enzyme activation and inhibition having therapeutic potential. The rate of cholesterol 24-hydroxylation determines the rate of brain cholesterol turnover and the rate of sterol flux through the plasma membranes. The latter was shown to affect membrane properties and thereby membrane proteins and membrane-dependent processes. Previously we found that treatment of 5XFAD mice, an Alzheimer’s disease model, with a small dose of anti-HIV drug efavirenz allosterically activated cytochrome P450 46A1 in the brain and mitigated several disease manifestations. Herein, we generated Cyp46a1−/−5XFAD mice and treated them, along with 5XFAD animals, with efavirenz to ascertain cytochrome P450 46A1-dependent and independent drug effects. Efavirenz-treated versus control Cyp46a1−/−5XFAD and 5XFAD mice were compared for the brain sterol and steroid hormone content, amyloid β burden, protein and mRNA expression as well as synaptic ultrastructure. We found that the cytochrome P450 46A1-dependent efavirenz effects included changes in the levels of brain sterols, steroid hormones, and such proteins as glial fibrillary acidic protein, Iba1, Munc13-1, post-synaptic density-95, gephyrin, synaptophysin and synapsin-1. Changes in the expression of genes involved in neuroprotection, neurogenesis, synaptic function, inflammation, oxidative stress and apoptosis were also cytochrome P450 46A1-dependent. The total amyloid β load was the same in all groups of animals, except lack of cytochrome P450 46A1 decreased the production of the amyloid β40 species independent of treatment. In contrast, altered transcription of genes from cholinergic, monoaminergic, and peptidergic neurotransmission, steroid sulfation and production as well as vitamin D3 activation was the main CYP46A1-independent efavirenz effect. Collectively, the data obtained reveal that CYP46A1 controls cholesterol availability for the production of steroid hormones in the brain and the levels of biologically active neurosteroids. In addition, cytochrome P450 46A1 activity also seems to affect the levels of post-synaptic density-95, the main postsynaptic density protein, possibly by altering the calcium/calmodulin-dependent protein kinase II inhibitor 1 expression and activity of glycogen synthase kinase 3β. Even at a small dose, efavirenz likely acts as a transcriptional regulator, yet this regulation may not necessarily lead to functional effects. This study further confirmed that cytochrome P450 46A1 is a key enzyme for cholesterol homeostasis in the brain and that the therapeutic efavirenz effects on 5XFAD mice are likely realized via cytochrome P450 46A1 activation.

scholarly journals Pleiotropic neuroprotective effects of taxifolin in cerebral amyloid angiopathy

2019 ◽  
Vol 116 (20) ◽  
pp. 10031-10038 ◽  
Author(s):  
Takayuki Inoue ◽  
Satoshi Saito ◽  
Masashi Tanaka ◽  
Hajime Yamakage ◽  
Toru Kusakabe ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Amyloid Angiopathy ◽  
Apoptotic Cell ◽  
Amyloid Β ◽  
Myeloid Cell ◽  
Low Permeability ◽  
Amyloid Angiopathy ◽  
Neuroprotective Effects ◽  
Cerebral Amyloid ◽  
The Brain

Cerebral amyloid angiopathy (CAA) results from amyloid-β deposition in the cerebrovasculature. It is frequently accompanied by Alzheimer’s disease and causes dementia. We recently demonstrated that in a mouse model of CAA, taxifolin improved cerebral blood flow, promoted amyloid-β removal from the brain, and prevented cognitive dysfunction when administered orally. Here we showed that taxifolin inhibited the intracerebral production of amyloid-β through suppressing the ApoE–ERK1/2–amyloid-β precursor protein axis, despite the low permeability of the blood–brain barrier to taxifolin. Higher expression levels of triggering receptor expressed on myeloid cell 2 (TREM2) were associated with the exacerbation of inflammation in the brain. Taxifolin suppressed inflammation, alleviating the accumulation of TREM2-expressing cells in the brain. It also mitigated glutamate levels and oxidative tissue damage and reduced brain levels of active caspases, indicative of apoptotic cell death. Thus, the oral administration of taxifolin had intracerebral pleiotropic neuroprotective effects on CAA through suppressing amyloid-β production and beneficially modulating proinflammatory microglial phenotypes.

scholarly journals A State of the Art of Antioxidant Properties of Curcuminoids in Neurodegenerative Diseases

2021 ◽  
Vol 22 (6) ◽  
pp. 3168
Author(s):  
Serena Silvestro ◽  
Cinzia Sindona ◽  
Placido Bramanti ◽  
Emanuela Mazzon
Keyword(s):  
Oxidative Phosphorylation ◽  
Neurodegenerative Diseases ◽  
Neuronal Cells ◽  
Antioxidant Properties ◽  
Neuroprotective Effects ◽  
Energy Needs ◽  
Anti Oxidant ◽  
Therapeutic Properties ◽  
The Brain ◽  
Lateral Sclerosis

Neurodegenerative diseases represent a set of pathologies characterized by an irreversible and progressive, and a loss of neuronal cells in specific areas of the brain. Oxidative phosphorylation is a source of energy production by which many cells, such as the neuronal cells, meet their energy needs. Dysregulations of oxidative phosphorylation induce oxidative stress, which plays a key role in the onset of neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). To date, for most neurodegenerative diseases, there are no resolute treatments, but only interventions capable of alleviating the symptoms or slowing the course of the disease. Therefore, effective neuroprotection strategies are needed. In recent years, natural products, such as curcuminoids, have been intensively explored and studied for their therapeutic potentials in several neurodegenerative diseases. Curcuminoids are, nutraceutical compouns, that owen several therapeutic properties such as anti-oxidant, anti-inflammatory and neuroprotective effects. In this context, the aim of this review was to provide an overview of preclinical and clinical evidence aimed to illustrate the antioxidant effects of curcuminoids in neurodegenerative diseases. Promising results from preclinical studies encourage the use of curcuminoids for neurodegeneration prevention and treatment.

scholarly journals Traumatic Brain Injury Accelerates the Onset of Cognitive Dysfunction and Aggravates Alzheimer’s-like Pathology in the Hippocampus by Altering the Phenotype of Microglia in APP/PS1 Mouse Model

2020 ◽  
Author(s):  
Di Wu ◽  
Jay Prakash Prasad Kumal ◽  
Xiaodi Lu ◽  
Yixuan Li ◽  
Dongsheng Mao ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Mouse Model ◽  
Learning And Memory ◽  
Cell Density ◽  
Cognitive Dysfunction ◽  
Memory Function ◽  
Synaptic Function ◽  
Histopathological Study ◽  
The Brain

Abstract Background: There are increasing studies suggest that Traumatic Brain Injury(TBI) might be the cause of some neurodegenerative diseases, including Alzheimer’s Disease(AD). The mechanism of AD induced by TBI has also been elucidated from sorts of aspects. However, there are also researches which opponent to the viewpoint that TBI is the reason of AD. In this study, we investigate whether and how could TBI accelerated the Alzheimer’s-like pathology and cognitive dysfunction in APP/PS1 mice.Method: The traumatic brain injury model was established in adult male APP/PS1 and C57BL/6 mice. At the 29th and 30th day post-TBI, Novel object and novel position recognition test were performed to test the learning and memory function. After cognitive function test, all the mice were sacrificed with PBS perfusion to anatomize the brain for histopathological study. To determine whether the Alzheimer’s-like pathology and the synaptic function decline can be accelerated by TBI, HE staining, IF staining and IHC staining were performed to detect the cell density in the brain, the degree of Aβ-plaques deposition in the brain, and SYP expression in the brain. We also examined the activity and the phenotype of microglia by IF staining and western-blotting the after the 1st, 2nd, 3rd and 4th week of TBI.Result: In current study, we showed that, on the one hand, TBI impaired the hippocampal-dependent learning and memory, decreased the cell density in the brain, disturbed the synaptic function in the brain, aggravated Aβ-plaques deposition in the hippocampus. On the other hand, TBI also quickly activated microglia in the CNS and altered the phenotype of microglia polarizing to a pro-inflammatory direction. The duration of activation of microglia post-TBI can be at least 3 weeks. We also found that microglia activity was related to the deposition of Aβ-plaques in the specific region of hippocampus. Conclusion: Our experiment suggested that TBI accelerate the onset of cognitive dysfunction and Alzheimer’s-like pathology in APP/PS1 mouse model by altering microglia polarizing direction to mostly exhibiting pro-inflammatory phenotype.

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