Targeting Aggrephagy for the Treatment of Alzheimer’s Disease

Malampati, Sandeep; Song, Ju Xian; Tong, Benjamin Chun‐Kit; Nalluri, Anusha; Yang, Chuanbin; Wang, Ziying; Sreenivasmurthy, Sravan Gopalkrishnashetty; Zhu, Zhou; Liu, Jia; Su, Cheng-Fu; Krishnamoorthi, Senthilkumar; Iyaswamy, Ashok; Cheung, Kmc; Lu, Jia; Li, Min

doi:10.3390/cells9020311

Cited by 44 publications

(27 citation statements)

References 185 publications

(214 reference statements)

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“…The abnormal autophagosomes accumulation was also recently described in the distal region of axons in neurons of AD patients and animal models, and it was correlated with the impairment of retrograde transport along the axons and with changes in the autophagic clearance of the Aβ peptide [179]. This work is an example of many others showing the autophagy deficit in the "neuronal housekeeper" function by which lysosomes lose the capability to degrade aberrant proteins, thereby participating in the accumulation Aβ peptide and Tau [185][186][187][188][189][190][191][192][193].…”

Section: Lysosomes Dysfunction and Adsupporting

confidence: 67%

The Other Side of Alzheimer’s Disease: Influence of Metabolic Disorder Features for Novel Diagnostic Biomarkers

Argentati

Tortorella

Bazzucchi

et al. 2020

JPM

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Nowadays, the amyloid cascade hypothesis is the dominant model to explain Alzheimer’s disease (AD) pathogenesis. By this hypothesis, the inherited genetic form of AD is discriminated from the sporadic form of AD (SAD) that accounts for 85–90% of total patients. The cause of SAD is still unclear, but several studies have shed light on the involvement of environmental factors and multiple susceptibility genes, such as Apolipoprotein E and other genetic risk factors, which are key mediators in different metabolic pathways (e.g., glucose metabolism, lipid metabolism, energetic metabolism, and inflammation). Furthermore, growing clinical evidence in AD patients highlighted the presence of affected systemic organs and blood similarly to the brain. Collectively, these findings revise the canonical understating of AD pathogenesis and suggest that AD has metabolic disorder features. This review will focus on AD as a metabolic disorder and highlight the contribution of this novel understanding on the identification of new biomarkers for improving an early AD diagnosis.

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Section: Lysosomes Dysfunction and Adsupporting

confidence: 67%

The Other Side of Alzheimer’s Disease: Influence of Metabolic Disorder Features for Novel Diagnostic Biomarkers

Argentati

Tortorella

Bazzucchi

et al. 2020

JPM

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“…APP cleavage products that are present in MVBs can be targeted to the autophagic pathway through the generation of amphisomes [99]. The cytotoxic accumulation and aggregation of Aβ in endolysomes can also permeabilize the lysosomal membrane and lead to the release of Aβ in the cytosol (Figure 2, AD condition) and hence the subsequent clearance is likely to require aggrephagy [111]. Finally, lysophagy that allows the clearance of damaged lysosomes [112] would be of prime importance during AD to prevent the accumulation of damaged lysosomes (Figure 2, AD condition).…”

Section: Relevance Of Autophagy In Amyloid-associated Endosomal Dynamicsmentioning

confidence: 99%

Transmissible Endosomal Intoxication: A Balance between Exosomes and Lysosomes at the Basis of Intercellular Amyloid Propagation

2020

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In Alzheimer′s disease (AD), endolysosomal dysfunctions are amongst the earliest cellular features to appear. Each organelle of the endolysosomal system, from the multivesicular body (MVB) to the lysosome, contributes to the homeostasis of amyloid precursor protein (APP) cleavage products including β-amyloid (Aβ) peptides. Hence, this review will attempt to disentangle how changes in the endolysosomal system cumulate to the generation of toxic amyloid species and hamper their degradation. We highlight that the formation of MVBs and the generation of amyloid species are closely linked and describe how the molecular machineries acting at MVBs determine the generation and sorting of APP cleavage products towards their degradation or release in association with exosomes. In particular, we will focus on AD-related distortions of the endolysomal system that divert it from its degradative function to favour the release of exosomes and associated amyloid species. We propose here that such an imbalance transposed at the brain scale poses a novel concept of transmissible endosomal intoxication (TEI). This TEI would initiate a self-perpetuating transmission of endosomal dysfunction between cells that would support the propagation of amyloid species in neurodegenerative diseases.

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“…There are three protein quality systems have been found to degrade misfolded or aggregated protein, such as ubiquitinated proteasomal degradation, chaperone-mediated degradation, and selective autophagy or aggrephagy [3]. Previous studies have been demonstrated that an increasing trend in the number of AD-related proteins are associated with aggresome [4], and non-pathological proteins could form invasive inclusion bodies as well. It has been found that silencing the expression of ubiquitin ligase HRD1 in SH-SY5Y human neuroblastoma cells prevents the formation of APP [5], and ubiquitin 1 linked to AD is known to regulate presenilin-1, which plays a key role of invasiveness in AD pathogenesis [6].…”

Section: Introductionmentioning

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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Targeting Aggrephagy for the Treatment of Alzheimer’s Disease

Cited by 44 publications

References 185 publications

The Other Side of Alzheimer’s Disease: Influence of Metabolic Disorder Features for Novel Diagnostic Biomarkers

The Other Side of Alzheimer’s Disease: Influence of Metabolic Disorder Features for Novel Diagnostic Biomarkers

Transmissible Endosomal Intoxication: A Balance between Exosomes and Lysosomes at the Basis of Intercellular Amyloid Propagation

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

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