Roles and Mechanisms of the Protein Quality Control System in Alzheimer’s Disease

Liu, Yaping; Ding, Runrong; Xu, Ze; Xue, Yuan; Zhang, Dongdong; Zhang, Yujing; Li, Wenjie; Li, Xing

doi:10.3390/ijms23010345

Cited by 13 publications

(10 citation statements)

References 131 publications

(251 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Various pathogenic mechanisms have been proposed to work in conjunction with amyloid-β accumulation to help drive disease. These include the development of tau tangles, activated microglia producing proinflammatory mediators, mitochondrial dysfunction, and disruption of quality control mechanisms for proteins (e.g., autophagy, ubiquitin-proteasome) [ 4 , 8 , 10 , 11 , 12 ]. In addition, the ApoE genotype affects multiple components of pathogenesis (e.g., deposition and clearance of amyloid-β, tau hyperphosphorylation, blood–brain barrier dysfunction, and neuroinflammation) [ 3 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Exploring Whether Iron Sequestration within the CNS of Patients with Alzheimer’s Disease Causes a Functional Iron Deficiency That Advances Neurodegeneration

2023

View full text Add to dashboard Cite

The involvement of iron in the pathogenesis of Alzheimer’s disease (AD) may be multifaceted. Besides potentially inducing oxidative damage, the bioavailability of iron may be limited within the central nervous system, creating a functionally iron-deficient state. By comparing staining results from baseline and modified iron histochemical protocols, iron was found to be more tightly bound within cortical sections from patients with high levels of AD pathology compared to subjects with a diagnosis of something other than AD. To begin examining whether the bound iron could cause a functional iron deficiency, a protein-coding gene expression dataset of initial, middle, and advanced stages of AD from olfactory bulb tissue was analyzed for iron-related processes with an emphasis on anemia-related changes in initial AD to capture early pathogenic events. Indeed, anemia-related processes had statistically significant alterations, and the significance of these changes exceeded those for AD-related processes. Other changes in patients with initial AD included the expressions of transcripts with iron-responsive elements and for genes encoding proteins for iron transport and mitochondrial-related processes. In the latter category, there was a decreased expression for the gene encoding pitrilysin metallopeptidase 1 (PITRM1). Other studies have shown that PITRM1 has an altered activity in patients with AD and is associated with pathological changes in this disease. Analysis of a gene expression dataset from PITRM1-deficient or sufficient organoids also revealed statistically significant changes in anemia-like processes. These findings, together with supporting evidence from the literature, raise the possibility that a pathogenic mechanism of AD could be a functional deficiency of iron contributing to neurodegeneration.

show abstract

Section: Introductionmentioning

confidence: 99%

Exploring Whether Iron Sequestration within the CNS of Patients with Alzheimer’s Disease Causes a Functional Iron Deficiency That Advances Neurodegeneration

2023

View full text Add to dashboard Cite

show abstract

“…The clearance of physiological and pathological tau is mainly mediated by the ubiquitin proteasome system and autophagy/lysosomal degradation pathway. In AD patients, the neuronal lysosome system was dysregulated ( Sundelof et al, 2010 ; Wang X. M. et al, 2021 ; Liu et al, 2021 ; Hamano et al, 2021 ). The results of this study show that CR promotes the degradation of pathological tau mainly through the lysosome system rather than the proteasome system.…”

Section: Discussionmentioning

confidence: 99%

A Tau Pathogenesis-Based Network Pharmacology Approach for Exploring the Protections of Chuanxiong Rhizoma in Alzheimer’s Disease

Zeng

Qiu

et al. 2022

Front. Pharmacol.

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is the most common cause of neurodegenerative dementia and one of the top medical concerns worldwide. Currently, the approved drugs to treat AD are effective only in treating the symptoms, but do not cure or prevent AD. Although the exact causes of AD are not understood, it is recognized that tau aggregation in neurons plays a key role. Chuanxiong Rhizoma (CR) has been widely reported as effective for brain diseases such as dementia. Thus, we explored the protections of CR in AD by a tau pathogenesis–based network pharmacology approach. According to ultra-HPLC with triple quadrupole mass spectrometry data and Lipinski’s rule of five, 18 bioactive phytochemicals of CR were screened out. They were shown corresponding to 127 tau pathogenesis–related targets, among which VEGFA, IL1B, CTNNB1, JUN, ESR1, STAT3, APP, BCL2L1, PTGS2, and PPARG were identified as the core ones. We further analyzed the specific actions of CR-active phytochemicals on tau pathogenesis from the aspects of tau aggregation and tau-mediated toxicities. It was shown that neocnidilide, ferulic acid, coniferyl ferulate, levistilide A, Z-ligustilide, butylidenephthalide, and caffeic acid can be effective in reversing tau hyperphosphorylation. Neocnidilide, senkyunolide A, butylphthalide, butylidenephthalide, Z-ligustilide, and L-tryptophan may be effective in promoting lysosome-associated degradation of tau, and levistilide A, neocnidilide, ferulic acid, L-tryptophan, senkyunolide A, Z-ligustilide, and butylidenephthalide may antagonize tau-mediated impairments of intracellular transport, axon and synaptic damages, and neuron death (especially apoptosis). The present study suggests that acting on tau aggregation and tau-mediated toxicities is part of the therapeutic mechanism of CR against AD.

show abstract

“…Since the tau clearance rate in the neuron exceeds the tau release rate in the neuron by a factor of 10 4 ( Table 1 ), most tau is cleared by destruction (catabolism) rather than release. Catabolism of tau has been linked to the lysosomal and the proteasomal degradation systems (de Vrij et al, 2004 ; Chesser et al, 2013 ; Tarasoff-Conway et al, 2015 ; Vaz-Silva et al, 2018 ; Xin et al, 2018 ; Liu et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…Although there is evidence of increased cytosolic tau in Alzheimer's disease (Han et al, 2017 ; Koss et al, 2018 ), evidence of increased synthesis of tau in Alzheimer's disease is lacking. There is growing interest in how tau is catabolized in the Alzheimer's disease (de Vrij et al, 2004 ; Chesser et al, 2013 ; Tarasoff-Conway et al, 2015 ; Vaz-Silva et al, 2018 ; Xin et al, 2018 ; Liu et al, 2021 ). A decline in tau catabolism could explain elevated levels of tau in the brain, CSF, and plasma compartments.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, consensus is lacking on the cause of elevated tau levels in Alzheimer's disease. Rising levels of tau could be due to increased neuronal synthesis, increased neuronal release, decreased neuronal clearance, or impaired CSF clearance of tau (de Vrij et al, 2004 ; Yamada et al, 2011 , 2014 , 2015 ; Chai et al, 2012 ; Gendreau and Hall, 2013 ; Tarasoff-Conway et al, 2015 ; Orr et al, 2017 ; Merezhko et al, 2018 ; Vaz-Silva et al, 2018 ; Xin et al, 2018 ; Kitaguchi et al, 2019 ; Patel et al, 2019 ; Pernègre et al, 2019 ; Ruan and Ikezu, 2019 ; Strang et al, 2019 ; Brunello et al, 2020 ; Harrison et al, 2020 ; Nimmo et al, 2020 ; Liu et al, 2021 ; Ishida et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Tau kinetics in Alzheimer's disease

Hier

Azizi

Thimgan

et al. 2022

Front. Aging Neurosci.

View full text Add to dashboard Cite

The cytoskeletal protein tau is implicated in the pathogenesis of Alzheimer's disease which is characterized by intra-neuronal neurofibrillary tangles containing abnormally phosphorylated insoluble tau. Levels of soluble tau are elevated in the brain, the CSF, and the plasma of patients with Alzheimer's disease. To better understand the causes of these elevated levels of tau, we propose a three-compartment kinetic model (brain, CSF, and plasma). The model assumes that the synthesis of tau follows zero-order kinetics (uncorrelated with compartmental tau levels) and that the release, absorption, and clearance of tau is governed by first-order kinetics (linearly related to compartmental tau levels). Tau that is synthesized in the brain compartment can be released into the interstitial fluid, catabolized, or retained in neurofibrillary tangles. Tau released into the interstitial fluid can mix with the CSF and eventually drain to the plasma compartment. However, losses of tau in the drainage pathways may be significant. The kinetic model estimates half-life of tau in each compartment (552 h in the brain, 9.9 h in the CSF, and 10 h in the plasma). The kinetic model predicts that an increase in the neuronal tau synthesis rate or a decrease in tau catabolism rate best accounts for observed increases in tau levels in the brain, CSF, and plasma found in Alzheimer's disease. Furthermore, the model predicts that increases in brain half-life of tau in Alzheimer's disease should be attributed to decreased tau catabolism and not to increased tau synthesis. Most clearance of tau in the neuron occurs through catabolism rather than release to the CSF compartment. Additional experimental data would make ascertainment of the model parameters more precise.

show abstract

Roles and Mechanisms of the Protein Quality Control System in Alzheimer’s Disease

Cited by 13 publications

References 131 publications

Exploring Whether Iron Sequestration within the CNS of Patients with Alzheimer’s Disease Causes a Functional Iron Deficiency That Advances Neurodegeneration

Exploring Whether Iron Sequestration within the CNS of Patients with Alzheimer’s Disease Causes a Functional Iron Deficiency That Advances Neurodegeneration

A Tau Pathogenesis-Based Network Pharmacology Approach for Exploring the Protections of Chuanxiong Rhizoma in Alzheimer’s Disease

Tau kinetics in Alzheimer's disease

Contact Info

Product

Resources

About