scholarly journals Exploring the Potential of Therapeutic Agents Targeted towards Mitigating the Events Associated with Amyloid-β Cascade in Alzheimer’s Disease

2020 ◽  
Vol 21 (20) ◽  
pp. 7443 ◽  
Author(s):  
Tapan Behl ◽  
Ishnoor Kaur ◽  
Ovidiu Fratila ◽  
Roxana Brata ◽  
Simona Bungau
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Therapeutic Agents ◽  
Active Immunotherapy ◽  
Amyloid Hypothesis ◽  
Neuronal Connections ◽  
Glucagon Like Peptide 1 ◽  
Natural Drugs ◽  
Enzymatic Pathways

One of the most commonly occurring neurodegenerative disorders, Alzheimer’s disease (AD), encompasses the loss of cognitive and memory potential, impaired learning, dementia and behavioral defects, and has been prevalent since the 1900s. The accelerating occurrence of AD is expected to reach 65.7 million by 2030. The disease results in neural atrophy and disrupted inter-neuronal connections. Amongst multiple AD pathogenesis hypotheses, the amyloid beta (Aβ) cascade is the most relevant and accepted form of the hypothesis, which suggests that Aβ monomers are formed as a result of the cleavage of amyloid precursor protein (APP), followed by the conversion of these monomers to toxic oligomers, which in turn develop β-sheets, fibrils and plaques. The review targets the events in the amyloid hypothesis and elaborates suitable therapeutic agents that function by hindering the steps of plaque formation and lowering Aβ levels in the brain. The authors discuss treatment possibilities, including the inhibition of β- and γ-secretase-mediated enzymatic cleavage of APP, the immune response generating active immunotherapy and passive immunotherapeutic approaches targeting monoclonal antibodies towards Aβ aggregates, the removal of amyloid aggregates by the activation of enzymatic pathways or the regulation of Aβ circulation, glucagon-like peptide-1 (GLP-1)-mediated curbed accumulation and the neurotoxic potential of Aβ aggregates, bapineuzumab-mediated vascular permeability alterations, statin-mediated Aβ peptide degradation, the potential role of ibuprofen and the significance of natural drugs and dyes in hindering the amyloid cascade events. Thus, the authors aim to highlight the treatment perspective, targeting the amyloid hypothesis, while simultaneously emphasizing the need to conduct further investigations, in order to provide an opportunity to neurologists to develop novel and reliable treatment therapies for the retardation of AD progression.

scholarly journals P2-293: Platinum-based inhibitors of amyloid-β as therapeutic agents for Alzheimer's disease

2008 ◽  
Vol 4 ◽  
pp. T458-T458
Author(s):  
Kevin J. Barnham ◽  
Vijaya B. Kenche ◽  
Giuseppe D. Ciccotosto ◽  
David P. Smith ◽  
Deborah J. Tew ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Therapeutic Agents

Active Amyloid-β Vaccination Results in Epigenetic Changes in the Hippocampus of an Alzheimer’s Disease-Like Mouse Model

2019 ◽  
Vol 16 (9) ◽  
pp. 861-870 ◽  
Author(s):  
Roy Lardenoije ◽  
Daniël L.A. van den Hove ◽  
Sophie E. Jung ◽  
Monique Havermans ◽  
Peter Blackburn ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Amyloid Β ◽  
Active Immunization ◽  
Active Immunotherapy ◽  
Dna Hydroxymethylation ◽  
Synaptic Markers ◽  
The Impact

Background: While evidence accumulates for a role of epigenetic modifications in the pathophysiological cascade of Alzheimer’s disease (AD), amyloid-β (Aβ)-targeted active immunotherapy approaches are under investigation to prevent or slow the progression of AD. The impact of Aβ active vaccines on epigenetic markers has not been studied thus far. Objective: The current study aims to establish the relationship between active immunotherapy with a MER5101-based vaccine (consisting of Aβ1-15 copies conjugated with a 7 aa spacer to the diphtheria toxoid carrier protein, formulated in a Th2-biased adjuvant) and epigenetic DNA modifications in the hippocampus of APPswe/PS1dE9 mice. Methods: As we previously reported, immunotherapy started when the mice were 10 months of age and behavioral testing occurred at 14 months of age, after which the mice were sacrificed for further analysis of their brains. In this add-on study, global levels of DNA methylation and hydroxymethylation, and DNA methyltransferase 3A (DNMT3A) were determined using quantitative immunohistochemistry, and compared to our previously analyzed immunization-induced changes in AD-related neuropathology and cognition. Results: Active immunization did not affect global DNA methylation levels but instead, resulted in decreased DNA hydroxymethylation and DNMT3A levels. Independent of immunization, inverse correlations with behavioral performance were observed for levels of DNA methylation and hydroxymethylation, as well as DNMT3A, while Aβ pathology and synaptic markers did not correlate with DNA methylation levels but did positively correlate with DNA hydroxymethylation and levels of DNMT3A. Conclusion: Our results indicate that active Aβ vaccination has significant effects on the epigenome in the hippocampus of APPswe/PS1dE9 mice, and suggest that DNA methylation and hydroxymethylation may be involved in cognitive functioning.

scholarly journals Glucagon-like Peptide 1, Brain, Neurodegenerative Diseases: A Modern View

2020 ◽  
Vol 6 (4) ◽  
pp. 153-172
Author(s):  
Bulgakova ◽  
Romanchuk ◽  
Treneva
Keyword(s):  
Alzheimer’S Disease ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Receptor Agonists ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide 1, a hormone synthesized in the intestine, has attracted the attention of scientists with its connection with the brain. A number of studies have shown the effect of glucagon-like peptide 1 on the functions of the nervous system, such as thermogenesis, blood pressure control, energy homeostasis, neurogenesis. In addition, modulation of glucagon-like peptide 1 activity may affect the aggregation of amyloid β-peptide in Alzheimer’s disease and dopamine in Parkinson’s disease. Glucagon-like peptide 1 receptor agonists have shown a beneficial effect on animal brain ischemia by reducing the area of brain infarction, reducing neurological deficit due to inhibition of oxidative stress, apoptosis, and inflammatory response. Their positive effect on cognitive function in animals with type 2 diabetes mellitus or obesity has been proven, improving learning and memory. There is increasing evidence of the neuroprotective effect of glucagon-like peptide 1 receptor agonists in animals with neurodegenerative diseases, regardless of the presence of T2DM. However, further clinical studies are needed to study the feasibility of using these drugs to treat Parkinson’s disease, Alzheimer’s disease, and other forms of cognitive impairment in humans. The discussion of the above issues is the subject of this literature review.

Copper Imbalance in Alzheimer’s Disease and Its Link with the Amyloid Hypothesis: Towards a Combined Clinical, Chemical, and Genetic Etiology

2021 ◽  
pp. 1-19
Author(s):  
Rosanna Squitti ◽  
Peter Faller ◽  
Christelle Hureau ◽  
Alberto Granzotto ◽  
Anthony R. White ◽  
...  
Keyword(s):  
Risk Factors ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Metal Ion ◽  
Amyloid Β ◽  
High Energy ◽  
Amyloid Β Protein ◽  
Amyloid Hypothesis ◽  
Clinical Chemical

The cause of Alzheimer’s disease (AD) is incompletely defined. To date, no mono-causal treatment has so far reached its primary clinical endpoints, probably due to the complexity and diverse neuropathology contributing to the neurodegenerative process. In the present paper, we describe the plausible etiological role of copper (Cu) imbalance in the disease. Cu imbalance is strongly associated with neurodegeneration in dementia, but a complete biochemical etiology consistent with the clinical, chemical, and genetic data is required to support a causative association, rather than just correlation with disease. We hypothesize that a Cu imbalance in the aging human brain evolves as a gradual shift from bound metal ion pools, associated with both loss of energy production and antioxidant function, to pools of loosely bound metal ions, involved in gain-of-function oxidative stress, a shift that may be aggravated by chemical aging. We explain how this may cause mitochondrial deficits, energy depletion of high-energy demanding neurons, and aggravated protein misfolding/oligomerization to produce different clinical consequences shaped by the severity of risk factors, additional comorbidities, and combinations with other types of pathology. Cu imbalance should be viewed and integrated with concomitant genetic risk factors, aging, metabolic abnormalities, energetic deficits, neuroinflammation, and the relation to tau, prion proteins, α-synuclein, TAR DNA binding protein-43 (TDP-43) as well as systemic comorbidity. Specifically, the Amyloid Hypothesis is strongly intertwined with Cu imbalance because amyloid-β protein precursor (AβPP)/Aβ are probable Cu/Zn binding proteins with a potential role as natural Cu/Zn buffering proteins (loss of function), and via the plausible pathogenic role of Cu-Aβ.

Enantiomers of cysteine-modified SeNPs (d/lSeNPs) as inhibitors of metal-induced Aβ aggregation in Alzheimer's disease

2015 ◽  
Vol 3 (39) ◽  
pp. 7764-7774 ◽  
Author(s):  
Xianbo Zhou ◽  
Jing Sun ◽  
Tiantian Yin ◽  
Fangling Le ◽  
Licong Yang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Therapeutic Agents ◽  
Amyloid Β Peptide ◽  
Chiral Molecules ◽  
Aβ Aggregation ◽  
Potential Use

Chiral molecules, which selectively target and inhibit amyloid β-peptide (Aβ) aggregation, have potential use as therapeutic agents for the treatment of Alzheimer's disease (AD).

scholarly journals Liraglutide improves cognitive function by reducing amyloid-beta peptide accumulation and inhibiting inflammation in 5×FAD mice

2021 ◽  
Author(s):  
Liqin Qi ◽  
Lijing Lin ◽  
Jiaping Zheng ◽  
Xiaoying Liu ◽  
Xiaohong Liu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Function ◽  
Cognitive Ability ◽  
Amyloid Β ◽  
Pyramidal Cells ◽  
Underlying Mechanism ◽  
Ultrastructural Changes ◽  
Amyloid Β Protein ◽  
Glucagon Like Peptide 1

Abstract The glucagon-like peptide-1 analog, liraglutide, has been shown to be effective in Alzheimer’s disease (AD); however, the underlying mechanism remains unknown. In this study, we evaluated the effects of liraglutide (25 nmol/day for 8 weeks) on the cognitive ability of 12-month-old 5× familial Alzheimer’s disease (FAD) mice. The spatial cognitive ability was improved in 5×FAD mice after administration of liraglutide, associated with an increased number of pyramidal cells in the cortex and hippocampus. Liraglutide also alleviated the ultrastructural changes in chemical synapses and pyramidal cells and reduced local and universal inflammation in AD mice. Furthermore, liraglutide reduced the expression of amyloid β protein through the regulation of nuclear factor kappa B/beta-secretase 1 pathways in AD mice. The potential of liraglutide to improve the cognitive function in AD animals offers an effective pharmacological approach for treating neurodegenerative diseases.

Anti-Amyloid Aggregating Gold Nanoparticles: Can they Really be Translated from Bench to Bedside for Alzheimer's Disease Treatment?

2020 ◽  
Vol 21 (12) ◽  
pp. 1184-1192
Author(s):  
Sibhghatulla Shaikh ◽  
Nazia Nazam ◽  
Syed Mohd Danish Rizvi ◽  
Talib Hussain ◽  
Aisha Farhana ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gold Nanoparticles ◽  
Treatment Strategy ◽  
Amyloid Β ◽  
Therapeutic Agents ◽  
Current Status ◽  
Amyloid Β Protein ◽  
Appropriate Treatment ◽  
Β Protein

: Alzheimer’s disease (AD) is characterized by deposition of amyloid-β protein aggregates and an appropriate treatment strategy is urgently needed, as the number of diagnosed cases continues to increase. The management of AD and other brain-associated diseases is limited by the blood brain barrier and its selective control of drug passage. In fact, most of the promising drugs have restricted curative effects on AD owing to their lower bioavailability. Gold nanoparticles (AuNPs) have emerged as attractive therapeutic agents and have distinctive properties that could contribute to the development of a novel treatment strategy for neurodegenerative disorders. In this review article, we attempt to identify promising ways of developing competent AD therapeutic agents from anti-amyloid aggregating AuNPs. Initially, we discuss the current status of anti-amyloid inhibitors, the abilities of AuNPs to inhibit amyloid aggregation, and mechanistic aspects, and then describe plausible modifications that could aid the translation of AuNP-based therapeutics into neuromedicines. The review highlights some interesting characteristics that might effectively bridge the gap between laboratory and bedside treatments.

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