ER stress and UPR in Alzheimer’s disease: mechanisms, pathogenesis, treatments

Ajoolabady, Amir; Lindholm, Dan; Ren, Jun; Praticò, Domenico

doi:10.1038/s41419-022-05153-5

Cited by 86 publications

(83 citation statements)

References 139 publications

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“…In routine function, the ER stress signaling activates the unfolded protein response to reduce the volume of unfolded protein load and to help maintain normal cell function and metabolism [ 131 ]. However, chronic or extreme ER stress can trigger cell death by apoptosis and has been linked to many diseases such as cancer, diabetes, and neurodegenerative disorders [ 132 , 133 , 134 , 135 , 136 ].…”

Section: Pp Mechanisms Of Action As An Anti-cancer Agentmentioning

confidence: 99%

Pyrvinium Pamoate: Past, Present, and Future as an Anti-Cancer Drug

Schultz

2022

Biomedicines

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Pyrvinium, a lipophilic cation belonging to the cyanine dye family, has been used in the clinic as a safe and effective anthelminthic for over 70 years. Its structure, similar to some polyaminopyrimidines and mitochondrial-targeting peptoids, has been linked with mitochondrial localization and targeting. Over the past two decades, increasing evidence has emerged showing pyrvinium to be a strong anti-cancer molecule in various human cancers in vitro and in vivo. This efficacy against cancers has been attributed to diverse mechanisms of action, with the weight of evidence supporting the inhibition of mitochondrial function, the WNT pathway, and cancer stem cell renewal. Despite the overwhelming evidence demonstrating the efficacy of pyrvinium for the treatment of human cancers, pyrvinium has not yet been repurposed for the treatment of cancers. This review provides an in-depth analysis of the history of pyrvinium as a therapeutic, the rationale and data supporting its use as an anticancer agent, and the challenges associated with repurposing pyrvinium as an anti-cancer agent.

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Section: Pp Mechanisms Of Action As An Anti-cancer Agentmentioning

confidence: 99%

Pyrvinium Pamoate: Past, Present, and Future as an Anti-Cancer Drug

Schultz

2022

Biomedicines

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“…approaches have been developed to mitigate ER stress with few being tested in clinical trials [60]. Our data indicate that, without direct targeting the UPR or ER stress mechanisms, CP2 treatment reduced both, further strengthening therapeutic potential of this strategy.…”

Section: Supplementary Materialsmentioning

confidence: 66%

“…Here, we re-analyzed these data and demonstrated the presence of UPR and ER stress, which was reduced by CP2 treatment, further supporting translational value of this mouse model. The ER stress is commonly defined as a response to the build-up of unfolded or misfolded proteins within the ER, affecting the ER and cellular homeostasis [60]. Recent data also suggest the reciprocal relationship between abnormal mitochondria-ER communication and ER stress, which contributes to the onset and development of AD.…”

Section: Discussionmentioning

confidence: 99%

Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice

Panes¹,

Nguyen²,

Gao³

et al. 2023

Preprint

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Alzheimer’s Disease (AD) has no cure. Earlier, we showed that partial inhibition of mitochondrial complex I (MCI) with small molecule CP2 induces adaptive stress response activating multiple neuroprotective mechanisms. Chronic treatment reduced inflammation, improved synaptic and mitochondrial functions, and blocked neurodegeneration in symptomatic APP/PS1 mice, a translational model of AD. Here, using serial block-face scanning electron microscopy (SBFSEM) and three-dimensional (3D) EM reconstructions combined with Western blot analysis and next-generation RNA sequencing, we demonstrate that CP2 treatment also restores mitochondrial morphology and mitochondria-endoplasmic reticulum (ER) communication in the APP/PS1 mouse brain. Using 3D EM volume reconstructions, we show that mitochondria in AD dendrites exist primarily as mitochondria-on-a-string (MOAS). Compared to other morphological phenotypes, MOAS are extensively enveloped in the ER membranes forming multiple mitochondria-ER contact sites (MERCS) known to contribute to abnormal lipid and calcium homeostasis. CP2 treatment specifically reduced MOAS formation, consistent with improved energy homeostasis in the brain, with concomitant reduction in MERCS, ER stress, and improved lipid homeostasis. These data provide novel information on the role MOAS play in AD and additional support for further development of partial MCI inhibitors as disease modifying strategy for AD.

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“…Among three arms of UPR in ER stress conditions, the PERK pathway is the most well-studied in the neuroprotective effects of inhibition of ER stress. In parallel with this, Salubrinal, an anti-ER stress compound, has 10.3389/fncel.2023.1105247 been well investigated in neurodegenerative disease pathology and treatment (Gupta S. et al, 2021;Ajoolabady et al, 2022). Salubrinal is an activator of UPR, which raises ER chaperone levels, including BiP.…”

Section: Targeting Er Stress-induced Apoptotic Cell Deathmentioning

confidence: 99%

The neuroprotective effects of targeting key factors of neuronal cell death in neurodegenerative diseases: The role of ER stress, oxidative stress, and neuroinflammation

Karvandi

Hesari

Aref

et al. 2023

Front. Cell. Neurosci.

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Neuronal loss is one of the striking causes of various central nervous system (CNS) disorders, including major neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and Amyotrophic lateral sclerosis (ALS). Although these diseases have different features and clinical manifestations, they share some common mechanisms of disease pathology. Progressive regional loss of neurons in patients is responsible for motor, memory, and cognitive dysfunctions, leading to disabilities and death. Neuronal cell death in neurodegenerative diseases is linked to various pathways and conditions. Protein misfolding and aggregation, mitochondrial dysfunction, generation of reactive oxygen species (ROS), and activation of the innate immune response are the most critical hallmarks of most common neurodegenerative diseases. Thus, endoplasmic reticulum (ER) stress, oxidative stress, and neuroinflammation are the major pathological factors of neuronal cell death. Even though the exact mechanisms are not fully discovered, the notable role of mentioned factors in neuronal loss is well known. On this basis, researchers have been prompted to investigate the neuroprotective effects of targeting underlying pathways to determine a promising therapeutic approach to disease treatment. This review provides an overview of the role of ER stress, oxidative stress, and neuroinflammation in neuronal cell death, mainly discussing the neuroprotective effects of targeting pathways or molecules involved in these pathological factors.

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ER stress and UPR in Alzheimer’s disease: mechanisms, pathogenesis, treatments

Cited by 86 publications

References 139 publications

Pyrvinium Pamoate: Past, Present, and Future as an Anti-Cancer Drug

Pyrvinium Pamoate: Past, Present, and Future as an Anti-Cancer Drug

Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice

The neuroprotective effects of targeting key factors of neuronal cell death in neurodegenerative diseases: The role of ER stress, oxidative stress, and neuroinflammation

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