Emerging Proof of Protein Misfolding and Interactions in Multifactorial Alzheimer's Disease

Uddin, Sahab; Mamun, Abdullah Al; Rahman, Md. Ataur; Behl, Tapan; Perveen, Asma; Hafeez, Abdul; Bin-Jumah, May; Abdel-Daim, Mohamed M.; Ashraf, Ghulam Md

doi:10.2174/1568026620666200601161703

Cited by 49 publications

(31 citation statements)

References 135 publications

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“…Autophagy enhancers that can be utilized for the potential treatment of neurodegenerative diseases is receiving growing attention in recent studies [9,18,93,94]. It has been shown that the inactivation of mTOR by the lipophilic macrolide antibiotic rapamycin promotes the induction of autophagy [95].…”

Section: Discussionmentioning

confidence: 99%

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

Rahman¹,

Rahman²,

Mamun-Or-Rashid³

et al. 2021

Preprint

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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.

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Section: Discussionmentioning

confidence: 99%

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

Rahman¹,

Rahman²,

Mamun-Or-Rashid³

et al. 2021

Preprint

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“…Considering that autophagy is involved in the degradation of abnormal protein aggregates and the clearance of misfolded proteins [6,[73][74][75], the stimulation of autophagic activity may serve as an effective approach in treating neurodegenerative disorders [18,76,77]. Therefore, based on the role of OGT inhibitors in facilitating autophagic activity in cortical neurons, we propose the modulation of O-GlcNAcylation levels by OGT inhibition as a potential therapeutic approach to prevent and treat neurodegenerative disorders associated with a deficit in the autophagy process.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Inhibition of O-GlcNAc Transferase Promotes mTOR-Dependent Autophagy in Rat Cortical Neurons

et al. 2020

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O-GlcNAc transferase (OGT) is a ubiquitous enzyme that regulates the addition of β-N-acetylglucosamine (O-GlcNAc) to serine and threonine residues of target proteins. Autophagy is a cellular process of self-digestion, in which cytoplasmic resources, such as aggregate proteins, toxic compounds, damaged organelles, mitochondria, and lipid molecules, are degraded and recycled. Here, we examined how three different OGT inhibitors, alloxan, BXZ2, and OSMI-1, modulate O-GlcNAcylation in rat cortical neurons, and their autophagic effects were determined by immunoblot and immunofluorescence assays. We found that the treatment of cortical neurons with an OGT inhibitor decreased O-GlcNAcylation levels and increased LC3-II expression. Interestingly, the pre-treatment with rapamycin, an mTOR inhibitor, further increased the expression levels of LC3-II induced by OGT inhibition, implicating the involvement of mTOR signaling in O-GlcNAcylation-dependent autophagy. In contrast, OGT inhibitor-mediated autophagy was significantly attenuated by 3-methyladenine (3-MA), a blocker of autophagosome formation. However, when pre-treated with chloroquine (CQ), a lysosomotropic agent and a late-stage autophagy inhibitor, OGT inhibitors significantly increased LC3-II levels along with LC3 puncta formation, indicating the stimulation of autophagic flux. Lastly, we found that OGT inhibitors significantly decreased the levels of the autophagy substrate p62/SQSTM1 while increasing the expression of lysosome-associated membrane protein 1 (LAMP1). Together, our study reveals that the modulation of O-GlcNAcylation by OGT inhibition regulates mTOR-dependent autophagy in rat cortical neurons.

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“…Moreover, distinct biomarkers, which are essential to figure out the pathological characteristics of AD, have been observed in the cerebrospinal fluid (CSF) [9,10]. The advancement of AD is associated with three cardinal neuropathological features such as extracellular deposition of amyloid-β (Aβ) to produce neuritic plaques, intracellular neurofibrillary tangles (NFTs) and synaptic degeneration [11][12][13]. These pathological alterations arise in the neocortex, hippocampus, and other subcortical regions that are crucial for cognitive functions [14].…”

Section: Introductionmentioning

confidence: 99%

Revisiting the Amyloid Cascade Hypothesis: From Anti-Aβ Therapeutics to Auspicious New Ways for Alzheimer’s Disease

Uddin

Kabir

Rahman

et al. 2020

IJMS

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Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder related to age, characterized by the cerebral deposition of fibrils, which are made from the amyloid-β (Aβ), a peptide of 40–42 amino acids. The conversion of Aβ into neurotoxic oligomeric, fibrillar, and protofibrillar assemblies is supposed to be the main pathological event in AD. After Aβ accumulation, the clinical symptoms fall out predominantly due to the deficient brain clearance of the peptide. For several years, researchers have attempted to decline the Aβ monomer, oligomer, and aggregate levels, as well as plaques, employing agents that facilitate the reduction of Aβ and antagonize Aβ aggregation, or raise Aβ clearance from brain. Unluckily, broad clinical trials with mild to moderate AD participants have shown that these approaches were unsuccessful. Several clinical trials are running involving patients whose disease is at an early stage, but the preliminary outcomes are not clinically impressive. Many studies have been conducted against oligomers of Aβ which are the utmost neurotoxic molecular species. Trials with monoclonal antibodies directed against Aβ oligomers have exhibited exciting findings. Nevertheless, Aβ oligomers maintain equivalent states in both monomeric and aggregation forms; so, previously administered drugs that precisely decrease Aβ monomer or Aβ plaques ought to have displayed valuable clinical benefits. In this article, Aβ-based therapeutic strategies are discussed and several promising new ways to fight against AD are appraised.

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Emerging Proof of Protein Misfolding and Interactions in Multifactorial Alzheimer's Disease

Cited by 49 publications

References 135 publications

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

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

Pharmacological Inhibition of O-GlcNAc Transferase Promotes mTOR-Dependent Autophagy in Rat Cortical Neurons

Revisiting the Amyloid Cascade Hypothesis: From Anti-Aβ Therapeutics to Auspicious New Ways for Alzheimer’s Disease

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