scholarly journals Emerging Potential Role of Autophagy to Modulate Aggresome Formation: Insights Molecular Treatment of Alzheimer’s Disease

2021 ◽  
Author(s):  
Md. Ataur Rahman ◽  
MD. Hasanur Rahman ◽  
ANM Mamun-Or-Rashid ◽  
Hongik Hwang ◽  
Hyewhon Rhim
Keyword(s):  
Small Molecules ◽  
Potential Role ◽  
Senile Plaques ◽  
Memory Deficits ◽  
Brain Regions ◽  
Cellular Protection ◽  
Autophagy Pathway ◽  
Aggresome Formation ◽  
Ad Prevention

Alzheimer’s disease (AD) is one of the most prevailing neurodegenerative diseases in the world, which is characterized by memory dysfunction and the formation of tau and amyloid β (Aβ) aggregate in multiple brain regions, including the hippocampus and cortex. The formation of senile plaques involving tau hyperphosphorylation, fibrillar Aβ, and neurofibrillary tangles (NFTs) are used as pathological markers of AD, and eventually produces aggregation or misfolded protein. Importantly, it has been found that failure to degrade these aggregate-prone proteins leads to pathological consequences, such as synaptic impairment, cytotoxicity, neuronal atrophy, and memory deficits associated with AD. Recently, increasing evidences have been suggested that autophagy pathway plays a role as a central cellular protection system to prevent the toxicity induced by aggregate or misfolded proteins. Moreover, it has also been related that AD-related protein aggresomes could be selectively degraded by autophagosome and lysosomal fusion through autophagy pathway which is known as aggrephagy. Therefore, the regulation of autophagy might be served as a useful approach to modulate the formation of aggresome associated in AD. This review focuses on the recent improvements in the application of natural compounds and small molecules as a potential therapeutic approach for AD prevention and treatment via aggrephagy.

Hemodynamic responses and c-Fos changes associated with hypotensive hemorrhage: standardizing a protocol for severe hemorrhage in conscious rats

2007 ◽  
Vol 292 (5) ◽  
pp. R1862-R1871 ◽  
Author(s):  
Joslyn Ahlgren ◽  
Karen Porter ◽  
Linda F. Hayward
Keyword(s):  
Potential Role ◽  
Cardiovascular Response ◽  
Brain Regions ◽  
Total Blood Volume ◽  
Total Blood ◽  
Conscious Rats ◽  
Cuneiform Nucleus ◽  
Severe Hemorrhage ◽  
Lateral Nucleus

The central mechanisms underlying the transition from compensation to decompensation during severe hemorrhage (HEM) are poorly understood. Furthermore, a lack of consistency in HEM protocols exists in the current literature. This study assessed the cardiovascular response and Fos-like immunoreactivity (FLI) in specific brain regions following severe HEM at three rates (2, 1, or 0.5 ml·kg−1·min−1) in conscious rats. Heart rate (HR) and arterial pressure were recorded during the withdrawal of 30% of total blood volume (TBV). Data from animals hemorrhaged at the fast (F-HEM, n = 6), intermediate (I-HEM, n = 7), or slow (S-HEM, n = 7) rates were compared with saline (SAL, n = 5) and hypotensive (hydrazaline-induced, HYDRAZ, n = 5) controls. All HEM rates produced similar degrees of hypotension at the time of 30% TBV withdrawal. All HEM rates also produced bradycardia, but the change in HR was only significant in the F-HEM and I-HEM groups. Associated with I-HEM and F-HEM, but not HYDRAZ treatment were significant increases in FLI in the caudal ventrolateral periaqueductal gray (PAG), the central lateral nucleus of the rostral parabrachial nucleus, and locus coeruleus compared with SAL treatment. I-HEM also induced significant increases in FLI in the dorsomedial PAG, A7 region, and the cuneiform nucleus compared with SAL. S-HEM did not induce any significant change in FLI. Our results suggest that HEM at a rate of 1 ml·kg−1·min−1 may be most useful for investigating the potential role of the rostral brainstem regions in mediating hemorrhagic decompensation in conscious rats.

Exploring the Potential of Neuroproteomics in Alzheimer's Disease

2020 ◽  
Vol 20 (25) ◽  
pp. 2263-2278 ◽  
Author(s):  
Md. Sahab Uddin ◽  
Md. Tanvir Kabir ◽  
Md. Jakaria ◽  
Eduardo Sobarzo-Sánchez ◽  
George E. Barreto ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Targets ◽  
Senile Plaques ◽  
Brain Regions ◽  
Hyperphosphorylated Tau ◽  
Clinical Expression ◽  
Underlying Processes ◽  
With Memory

Alzheimer's disease (AD) is progressive brain amyloidosis that damages brain regions associated with memory, thinking, behavioral and social skills. Neuropathologically, AD is characterized by intraneuronal hyperphosphorylated tau inclusions as neurofibrillary tangles (NFTs), and buildup of extracellular amyloid-beta (Aβ) peptide as senile plaques. Several biomarker tests capturing these pathologies have been developed. However, for the full clinical expression of the neurodegenerative events of AD, there exist other central molecular pathways. In terms of understanding the unidentified underlying processes for the progression and development of AD, a complete comprehension of the structure and composition of atypical aggregation of proteins is essential. Presently, to aid the prognosis, diagnosis, detection, and development of drug targets in AD, neuroproteomics is elected as one of the leading essential tools for the efficient exploratory discovery of prospective biomarker candidates estimated to play a crucial role. Therefore, the aim of this review is to present the role of neuroproteomics to analyze the complexity of AD.

Roles of nitric oxide and angiotensin II in the impaired baroreflex gain of pregnancy

2007 ◽  
Vol 292 (6) ◽  
pp. R2179-R2187 ◽  
Author(s):  
Daisy L. Daubert ◽  
Dongmei Liu ◽  
Irving H. Zucker ◽  
Virginia L. Brooks
Keyword(s):  
Nitric Oxide ◽  
Angiotensin Ii ◽  
Potential Role ◽  
Brain Regions ◽  
Ventrolateral Medulla ◽  
Solitary Tract ◽  
Baroreflex Control ◽  
Protein Levels ◽  
Before And After

The present study tested the hypothesis that nitric oxide (NO) contributes to impaired baroreflex gain of pregnancy and that this action is enhanced by angiotensin II. To test these hypotheses, we quantified baroreflex control of heart rate in nonpregnant and pregnant conscious rabbits before and after: 1) blockade of NO synthase (NOS) with Nω-nitro-l-arginine (20 mg/kg iv); 2) blockade of the angiotensin II AT1 receptor with L-158,809 (5 μg·kg−1·min−1 iv); 3) infusion of angiotensin II (1 ng·kg−1·min−1 nonpregnant, 1.6–4 ng·kg−1·min−1 pregnant iv); 4) combined blockade of angiotensin II AT1 receptors and NOS; and 5) combined infusion of angiotensin II and blockade of NOS. To determine the potential role of brain neuronal NOS (nNOS), mRNA and protein levels were measured in the paraventricular nucleus, nucleus of the solitary tract, caudal ventrolateral medulla, and rostral ventrolateral medulla in pregnant and nonpregnant rabbits. The decrease in baroreflex gain observed in pregnant rabbits (from 23.3 ± 3.6 to 7.1 ± 0.9 beats·min−1·mmHg−1, P < 0.05) was not reversed by NOS blockade (to 8.3 ± 2.5 beats·min−1·mmHg−1), angiotensin II blockade (to 5.0 ± 1.1 beats·min−1·mmHg−1), or combined blockade (to 12.3 ± 4.8 beats·min−1·mmHg−1). Angiotensin II infusion with (to 5.7 ± 1.0 beats·min−1·mmHg−1) or without (to 8.4 ± 2.4 beats·min−1·mmHg−1) NOS blockade also failed to improve baroreflex gain in pregnant or nonpregnant rabbits. In addition, nNOS mRNA and protein levels in cardiovascular brain regions were not different between nonpregnant and pregnant rabbits. Therefore, we conclude that NO, either alone or via an interaction with angiotensin II, is not responsible for decrease in baroreflex gain during pregnancy.

scholarly journals Amyloid-β peptide induces oligodendrocyte death by activating the neutral sphingomyelinase–ceramide pathway

2004 ◽  
Vol 164 (1) ◽  
pp. 123-131 ◽  
Author(s):  
Jiunn-Tay Lee ◽  
Jan Xu ◽  
Jin-Moo Lee ◽  
Grace Ku ◽  
Xianlin Han ◽  
...  
Keyword(s):  
Antisense Oligonucleotides ◽  
Molecular Mechanisms ◽  
Potential Role ◽  
Neuronal Degeneration ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Neutral Sphingomyelinase ◽  
Ceramide Generation

Amyloid-β peptide (Aβ) accumulation in senile plaques, a pathological hallmark of Alzheimer's disease (AD), has been implicated in neuronal degeneration. We have recently demonstrated that Aβ induced oligodendrocyte (OLG) apoptosis, suggesting a role in white matter pathology in AD. Here, we explore the molecular mechanisms involved in Aβ-induced OLG death, examining the potential role of ceramide, a known apoptogenic mediator. Both Aβ and ceramide induced OLG death. In addition, Aβ activated neutral sphingomyelinase (nSMase), but not acidic sphingomyelinase, resulting in increased ceramide generation. Blocking ceramide degradation with N-oleoyl-ethanolamine exacerbated Aβ cytotoxicity; and addition of bacterial sphingomyelinase (mimicking cellular nSMase activity) induced OLG death. Furthermore, nSMase inhibition by 3-O-methyl-sphingomyelin or by gene knockdown using antisense oligonucleotides attenuated Aβ-induced OLG death. Glutathione (GSH) precursors inhibited Aβ activation of nSMase and prevented OLG death, whereas GSH depletors increased nSMase activity and Aβ-induced death. These results suggest that Aβ induces OLG death by activating the nSMase–ceramide cascade via an oxidative mechanism.

scholarly journals Soluble and insoluble dipeptide repeat protein measurements in C9orf72-frontotemporal dementia brains show regional differential solubility and correlation of poly-GR with clinical severity

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Annelies Quaegebeur ◽  
Idoia Glaria ◽  
Tammaryn Lashley ◽  
Adrian M. Isaacs
Keyword(s):  
Frontotemporal Dementia ◽  
Potential Role ◽  
Brain Regions ◽  
Clinical Severity ◽  
Repeat Proteins ◽  
Differential Solubility ◽  
Shed Light ◽  
Lateral Sclerosis ◽  
Dipeptide Repeat

Abstract A C9orf72 repeat expansion is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis. One of the suggested pathomechanisms is toxicity from dipeptide repeat proteins (DPRs), which are generated via unconventional translation of sense and antisense repeat transcripts with poly-GA, poly-GP and poly-GR being the most abundant dipeptide proteins. Animal and cellular studies highlight a neurotoxic role of poly-GR and poly-PR and to a lesser degree of poly-GA. Human post-mortem studies in contrast have been much less clear on a potential role of DPR toxicity but have largely focused on immunohistochemical methods to detect aggregated DPR inclusions. This study uses protein fractionation and sensitive immunoassays to quantify not only insoluble but also soluble poly-GA, poly-GP and poly-GR concentrations in brain homogenates of FTD patients with C9orf72 mutation across four brain regions. We show that soluble DPRs are less abundant in clinically affected areas (i.e. frontal and temporal cortices). In contrast, the cerebellum not only shows the largest DPR load but also the highest relative DPR solubility. Finally, poly-GR levels and poly-GP solubility correlate with clinical severity. These findings provide the first cross-comparison of soluble and insoluble forms of all sense DPRs and shed light on the distribution and role of soluble DPRs in the etiopathogenesis of human C9orf72-FTD.

scholarly journals The effect of insomnia on development of Alzheimer’s disease

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Shaghayegh Sadeghmousavi ◽  
Mahsa Eskian ◽  
Farzaneh Rahmani ◽  
Nima Rezaei
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Sleep Disorders ◽  
Potential Role ◽  
Neurodegenerative Disorder ◽  
Memory Deficits ◽  
Information Recall ◽  
Important Health ◽  
Important Health Issue

Abstract Alzheimer’s disease (AD) is the most common type of dementia and a neurodegenerative disorder characterized by memory deficits especially forgetting recent information, recall ability impairment, and loss of time tracking, problem-solving, language, and recognition difficulties. AD is also a globally important health issue but despite all scientific efforts, the treatment of AD is still a challenge. Sleep has important roles in learning and memory consolidation. Studies have shown that sleep deprivation (SD) and insomnia are associated with the pathogenesis of Alzheimer’s disease and may have an impact on the symptoms and development. Thus, sleep disorders have decisive effects on AD; this association deserves more attention in research, diagnostics, and treatment, and knowing this relation also can help to prevent AD through screening and proper management of sleep disorders. This study aimed to show the potential role of SD and insomnia in the pathogenesis and progression of AD.

scholarly journals The Functional Role of microRNAs in the Pathogenesis of Tauopathy

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2262
Author(s):  
Domenico Praticò
Keyword(s):  
Small Molecules ◽  
Tau Protein ◽  
Biological Fluids ◽  
Corticobasal Degeneration ◽  
Brain Regions ◽  
Post Translational Modifications ◽  
Master Regulators ◽  
Non Invasive ◽  
The Central Nervous System

Tauopathies are neurodegenerative disorders which include Alzheimer’s disease, Pick’s disease, corticobasal degeneration, and progressive supranuclear palsy among others. Pathologically, they are characterized by the accumulation of highly phosphorylated and aggregated tau protein in different brain regions. Currently, the mechanisms responsible for their pathogenesis are not known, and for this reason, there is no cure. MicroRNAs (miRNAs) are abundantly present in the central nervous system where they act as master regulators of pathways considered important for tau post-translational modifications, metabolism, and clearance. Although in recent years, several miRNAs have been reported to be altered in tauopathy, we still do not know whether these changes contribute to the onset and progression of the disorder, or are secondary events following the development of tau neuropathology. Additionally, since miRNAs are relatively stable in biological fluids and their measurement is easy and non-invasive, these small molecules hold the potential to function as biomarkers for tauopathy. Herein, we showcase recent findings on the biological link between miRNAs and the pathogenesis of tauopathy, and present emerging evidence supporting their role as biomarkers and targets for novel therapies against them.

POPDC proteins and cardiac function

2019 ◽  
Vol 47 (5) ◽  
pp. 1393-1404 ◽  
Author(s):  
Thomas Brand
Keyword(s):  
Potential Role ◽  
Striated Muscle ◽  
Short Review ◽  
Effector Proteins ◽  
Muscle Disease ◽  
Disease Genes ◽  
Protein Protein Interaction ◽  
Interaction Partners ◽  
And Function

Abstract The Popeye domain-containing gene family encodes a novel class of cAMP effector proteins in striated muscle tissue. In this short review, we first introduce the protein family and discuss their structure and function with an emphasis on their role in cyclic AMP signalling. Another focus of this review is the recently discovered role of POPDC genes as striated muscle disease genes, which have been associated with cardiac arrhythmia and muscular dystrophy. The pathological phenotypes observed in patients will be compared with phenotypes present in null and knockin mutations in zebrafish and mouse. A number of protein–protein interaction partners have been discovered and the potential role of POPDC proteins to control the subcellular localization and function of these interacting proteins will be discussed. Finally, we outline several areas, where research is urgently needed.

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