Role of siRNA-based nanocarriers for the treatment of neurodegenerative diseases

Among the compounds able to efficiently inhibit the amyloid aggregation of proteins and decompose the amyloid aggregates that cause neurodegenerative diseases, of particular interest are dendrimers, which represent individual macromolecules with the hypercrosslinked architectures and given molecular parameters. This short review outlines the peculiarities of the antiamyloid activity of dendrimers and discusses the effect of dendrimer structures and external factors on their antiamyloid properties. The potential of application of dendrimers in further investigations on the aggregation processes of amyloid proteins as the compounds that exhibit the remarkable antiamyloid activity is evaluated.

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The Role of Advanced Glycation End Products (AGEs) through the TRPA-1/NRF-2 Activation Pathway in the Neurodegenerative Diseases

10.33015/dominican.edu/2017.bio.05 ◽

2017 ◽

Author(s):

Sana Khateeb

Keyword(s):

Neurodegenerative Diseases ◽

Advanced Glycation End Products ◽

Advanced Glycation ◽

Activation Pathway ◽

Glycation End Products ◽

End Products

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Involvement of Heme Oxygenase-1 in Neuropsychiatric and Neurodegenerative Diseases

Current Pharmaceutical Design ◽

10.2174/1381612824666180717160623 ◽

2018 ◽

Vol 24 (20) ◽

pp. 2283-2302 ◽

Cited By ~ 9

Author(s):

Vivian B. Neis ◽

Priscila B. Rosa ◽

Morgana Moretti ◽

Ana Lucia S. Rodrigues

Keyword(s):

Neurodegenerative Diseases ◽

Heme Oxygenase ◽

Therapeutic Potential ◽

Redox Homeostasis ◽

Antioxidant Defenses ◽

Heme Oxygenase 1 ◽

Physiological Conditions ◽

And Oxidative Stress ◽

Defensive Mechanism

Heme oxygenase (HO) family catalyzes the conversion of heme into free iron, carbon monoxide and biliverdin. It possesses two well-characterized isoforms: HO-1 and HO-2. Under brain physiological conditions, the expression of HO-2 is constitutive, abundant and ubiquitous, whereas HO-1 mRNA and protein are restricted to small populations of neurons and neuroglia. HO-1 is an inducible enzyme that has been shown to participate as an essential defensive mechanism for neurons exposed to oxidant challenges, being related to antioxidant defenses in certain neuropathological conditions. Considering that neurodegenerative diseases (Alzheimer’s Disease (AD), Parkinson’s Disease (PD) and Multiple Sclerosis (MS)) and neuropsychiatric disorders (depression, anxiety, Bipolar Disorder (BD) and schizophrenia) are associated with increased inflammatory markers, impaired redox homeostasis and oxidative stress, conditions that may be associated with alterations in HO-levels/activity, the purpose of this review is to present evidence on the possible role of HO-1 in these Central Nervous System (CNS) diseases. In addition, the possible therapeutic potential of targeting brain HO-1 is explored in this review.

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Role of paraoxonase 1 (PON1) in organophosphate metabolism: Implications in neurodegenerative diseases

Toxicology and Applied Pharmacology ◽

10.1016/j.taap.2011.08.009 ◽

2011 ◽

Vol 256 (3) ◽

pp. 418-424 ◽

Cited By ~ 50

Author(s):

Vasilis P. Androutsopoulos ◽

Konstantinos Kanavouras ◽

Aristidis M. Tsatsakis

Keyword(s):

Neurodegenerative Diseases ◽

Paraoxonase 1

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Hypoxia, Acidification and Inflammation: Partners in Crime in Parkinson’s Disease Pathogenesis?

Immuno ◽

10.3390/immuno1020006 ◽

2021 ◽

Vol 1 (2) ◽

pp. 78-90

Author(s):

Johannes Burtscher ◽

Grégoire P. Millet

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neurodegenerative Diseases ◽

Current Knowledge ◽

Cell Types ◽

Brain Cell ◽

Special Focus ◽

Molecular Alterations ◽

Research Fields

Like in other neurodegenerative diseases, protein aggregation, mitochondrial dysfunction, oxidative stress and neuroinflammation are hallmarks of Parkinson’s disease (PD). Differentiating characteristics of PD include the central role of α-synuclein in the aggregation pathology, a distinct vulnerability of the striato-nigral system with the related motor symptoms, as well as specific mitochondrial deficits. Which molecular alterations cause neurodegeneration and drive PD pathogenesis is poorly understood. Here, we summarize evidence of the involvement of three interdependent factors in PD and suggest that their interplay is likely a trigger and/or aggravator of PD-related neurodegeneration: hypoxia, acidification and inflammation. We aim to integrate the existing knowledge on the well-established role of inflammation and immunity, the emerging interest in the contribution of hypoxic insults and the rather neglected effects of brain acidification in PD pathogenesis. Their tight association as an important aspect of the disease merits detailed investigation. Consequences of related injuries are discussed in the context of aging and the interaction of different brain cell types, in particular with regard to potential consequences on the vulnerability of dopaminergic neurons in the substantia nigra. A special focus is put on the identification of current knowledge gaps and we emphasize the importance of related insights from other research fields, such as cancer research and immunometabolism, for neurodegeneration research. The highlighted interplay of hypoxia, acidification and inflammation is likely also of relevance for other neurodegenerative diseases, despite disease-specific biochemical and metabolic alterations.

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Biobanking for Neurodegenerative Diseases: Challenge for Translational Research and Data Privacy

The Neuroscientist ◽

10.1177/10738584211036693 ◽

2021 ◽

pp. 107385842110366

Author(s):

Emilia Giannella ◽

Valentino Notarangelo ◽

Caterina Motta ◽

Giulia Sancesario

Keyword(s):

Neurodegenerative Diseases ◽

Translational Research ◽

Data Protection ◽

Biological Samples ◽

Data Privacy ◽

Neurological Diseases ◽

Great Effort ◽

General Data Protection Regulation ◽

In Silico Studies

Biobanking has emerged as a strategic challenge to promote knowledge on neurological diseases, by the application of translational research. Due to the inaccessibility of the central nervous system, the advent of biobanks, as structure collecting biospecimens and associated data, are essential to turn experimental results into clinical practice. Findings from basic research, omics sciences, and in silico studies, definitely require validation in clinically well-defined cohorts of patients, even more valuable when longitudinal, or including preclinical and asymptomatic individuals. Finally, collecting biological samples requires a great effort to guarantee respect for transparency and protection of sensitive data of patients and donors. Since the European General Data Protection Regulation 2016/679 has been approved, concerns about the use of data in biomedical research have emerged. In this narrative review, we focus on the essential role of biobanking for translational research on neurodegenerative diseases. Moreover, we address considerations for biological samples and data collection, the importance of standardization in the preanalytical phase, data protection (ethical and legal) and the role of donors in improving research in this field.

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Role of glial cells in the generation of sex differences in neurodegenerative diseases and brain aging

Mechanisms of Ageing and Development ◽

10.1016/j.mad.2021.111473 ◽

2021 ◽

pp. 111473

Author(s):

Julie A. Chowen ◽

Luis M. Garcia-Segura

Keyword(s):

Sex Differences ◽

Neurodegenerative Diseases ◽

Glial Cells ◽

Brain Aging

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Role of extracellular vesicles in neurodegenerative diseases

Progress in Neurobiology ◽

10.1016/j.pneurobio.2021.102022 ◽

2021 ◽

Vol 201 ◽

pp. 102022

Author(s):

Yun Xiao ◽

Shu-Kun Wang ◽

Yuan Zhang ◽

Abdolmohamad Rostami ◽

Anshel Kenkare ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Extracellular Vesicles

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AIF3 splicing switch triggers neurodegeneration

Molecular Neurodegeneration ◽

10.1186/s13024-021-00442-7 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Shuiqiao Liu ◽

Mi Zhou ◽

Zhi Ruan ◽

Yanan Wang ◽

Calvin Chang ◽

...

Keyword(s):

Cell Death ◽

Neurodegenerative Diseases ◽

Mitochondrial Dysfunction ◽

Nuclear Translocation ◽

Chromatin Condensation ◽

Neuronal Cell ◽

Adult Brain ◽

Postmortem Brain ◽

Mitochondrial Functions

Abstract Background Apoptosis-inducing factor (AIF), as a mitochondrial flavoprotein, plays a fundamental role in mitochondrial bioenergetics that is critical for cell survival and also mediates caspase-independent cell death once it is released from mitochondria and translocated to the nucleus under ischemic stroke or neurodegenerative diseases. Although alternative splicing regulation of AIF has been implicated, it remains unknown which AIF splicing isoform will be induced under pathological conditions and how it impacts mitochondrial functions and neurodegeneration in adult brain. Methods AIF splicing induction in brain was determined by multiple approaches including 5′ RACE, Sanger sequencing, splicing-specific PCR assay and bottom-up proteomic analysis. The role of AIF splicing in mitochondria and neurodegeneration was determined by its biochemical properties, cell death analysis, morphological and functional alterations and animal behavior. Three animal models, including loss-of-function harlequin model, gain-of-function AIF3 knockin model and conditional inducible AIF splicing model established using either Cre-loxp recombination or CRISPR/Cas9 techniques, were applied to explore underlying mechanisms of AIF splicing-induced neurodegeneration. Results We identified a nature splicing AIF isoform lacking exons 2 and 3 named as AIF3. AIF3 was undetectable under physiological conditions but its expression was increased in mouse and human postmortem brain after stroke. AIF3 splicing in mouse brain caused enlarged ventricles and severe neurodegeneration in the forebrain regions. These AIF3 splicing mice died 2–4 months after birth. AIF3 splicing-triggered neurodegeneration involves both mitochondrial dysfunction and AIF3 nuclear translocation. We showed that AIF3 inhibited NADH oxidase activity, ATP production, oxygen consumption, and mitochondrial biogenesis. In addition, expression of AIF3 significantly increased chromatin condensation and nuclear shrinkage leading to neuronal cell death. However, loss-of-AIF alone in harlequin or gain-of-AIF3 alone in AIF3 knockin mice did not cause robust neurodegeneration as that observed in AIF3 splicing mice. Conclusions We identified AIF3 as a disease-inducible isoform and established AIF3 splicing mouse model. The molecular mechanism underlying AIF3 splicing-induced neurodegeneration involves mitochondrial dysfunction and AIF3 nuclear translocation resulting from the synergistic effect of loss-of-AIF and gain-of-AIF3. Our study provides a valuable tool to understand the role of AIF3 splicing in brain and a potential therapeutic target to prevent/delay the progress of neurodegenerative diseases.

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