bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2022‒02‒06
fourteen papers selected by
Rich Giadone
Harvard University
  1. Advanced glycation end products in brain during aging.
  2. Defective proteostasis in patient-derived iPSC astrocytes and neurons carrying a MAPT IVS10+16 mutation.
  3. Overexpression of cellular stress proteins in skin fibroblast with presenilin 1 mutation.
  4. Pharmacologic IRE1/XBP1s activation promotes systemic adaptive remodeling in obesity.
  5. Contribution of ER stress to tau-mediated toxicity.
  6. Architecture of the endoplasmic reticulum plays a role in proteostasis.
  7. Large-scale deep multi-layer analysis of Alzheimer's disease brain reveals strong proteomic disease-related changes not observed at the RNA level.
  8. The protein-folding problem: Not yet solved.
  9. Loss of blood-brain barrier properties in association with endoplasmic reticulum stress in vascular cells from in vivo and in vitro models of Alzheimer's disease.
  10. iPSC-based disease modeling and drug discovery in cardinal neurodegenerative disorders.
  11. Neuroproteomics of cognitively healthy centenarians in the context of aging and Alzheimer's disease.
  12. Activation of autophagy attenuates motor deficits and extends lifespan in a C. elegans model of ALS.
  13. Endoplasmic reticulum stress induces mitochondrial dysfunction but not mitochondrial unfolded protein response in SH-SY5Y cells.
  14. Modelling the role of APOE4 in blood-brain barrier dysfunctions with isogenic IPSC-derived brain microvascular endothelial cells and pericytes.
  1. Chem Biol Interact. 2022 Jan 29. pii: S0009-2797(22)00045-X. [Epub ahead of print] 109840
    Advanced glycation end products in brain during aging.
    Utkarsh Reddy Addi, Sneha Jakhotia, S Sreenivasa Reddy, G Bhanuprakash Reddy.
      Aging is a main risk factor for many diseases including neurodegenerative disorders. Numerous theories and mechanisms including accumulation of advanced glycation end products (AGEs) have been put forward in explaining brain aging. However, a focused study on the status of AGEs in the brain during progressive aging in connection with interrelated cellular processes like ubiquitin-proteasome system (UPS), unfolded protein response, autophagy-lysosome system and apoptosis is lacking. Hence, in this study, we investigated the levels of AGEs in the brain of 5-, 10-, 15- and 20-months old WNIN rats. Endoplasmic reticulum (ER) stress response, UPS components, autophagy flux, neurotrophic and presynaptic markers along with cell death markers were analyzed by immunoblotting. The neuronal architecture was analyzed by H&E and Nissl staining. The results demonstrated progressive accumulation of AGEs in the brain during aging. Adaptive ER stress response was observed by 10-months while maladaptive ER stress response was seen at 15- and 20-months of age along with impaired UPS and autophagy, and perturbations in neuronal growth factors. All these disturbances intensify with age to further exaggerate cell death mechanisms. There was a shrinkage of the cell size with aging and Congo-red staining revealed β-amyloid accumulation in higher ages. Together these results suggest that progressive accumulation of AGEs with aging in the brain may lead to neuronal damage by affecting ER homeostasis, UPS, autophagic flux, and neuronal growth factors.
    Keywords:  Aging; Brain; ER stress; Glycation; Glycotoxins; Ubiquitin proteasome system; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.cbi.2022.109840
  2. Alzheimers Dement. 2021 Dec;17 Suppl 3 e054448
    Defective proteostasis in patient-derived iPSC astrocytes and neurons carrying a MAPT IVS10+16 mutation.
    Sidhartha Mahali, Rita Martinez, Miwei Hu, Jacob Marsh, Sally Temple, Celeste M Karch.
      BACKGROUND: Impaired proteostasis is associated with normal aging and is accelerated in neurodegeneration. This impairment may lead to the toxic accumulation of protein. In a subset of frontotemporal dementia (FTD) cases, mutations in the microtubule-associated protein tau (MAPT) that alter the relative levels of tau isoforms are sufficient to cause tau inclusions in neurons and astroglia and neurodegeneration without the presence of mutated protein (e.g. MAPTIVS10+16). However, the pathogenic events triggered by the expression of the alternatively spliced tau remain poorly understood.METHOD: To determine whether altered tau splicing induced from MAPT IVS10+16 mutations is sufficient to alter proteostasis in neurons and glia, we used human induced pluripotent stem cell (iPSC)-derived neurons and astrocytes from patients carrying the MAPT IVS10+16 mutation and CRISPR/Cas9, isogenic corrected controls.
    RESULT: We found that neurons from MAPT IVS10+16 carriers exhibited significantly higher levels of tau containing 4 microtubule binding repeats (4R tau), deficits in lysosomal trafficking, and acidity relative to isogenic-control neurons. Conversely, astrocytes from MAPT IVS10+16 carriers exhibited morphologically an increase in acidic lysosomes compared to isogenic-control astrocytes. Astrocytes from MAPT IVS10+16 carriers were also larger in size, consistent with cellular hypertrophy observed in brains from FTD-tau patients.
    CONCLUSION: Our findings suggest that altered tau splicing induced by the MAPT IVS10+16 mutation is sufficient to cause impaired lysosomal function and altered proteostasis in a cell-type specific manner.
    DOI:  https://doi.org/10.1002/alz.054448
  3. Alzheimers Dement. 2021 Dec;17 Suppl 3 e053170
    Overexpression of cellular stress proteins in skin fibroblast with presenilin 1 mutation.
    Gustavo Lopez-Toledo, Maria Del Carmen Silva-Lucero, Jose Antonio Arias-Montaño, Maria Del Carmen Cardenas-Aguayo.
      BACKGROUND: The accumulation and aggregation of misfolded proteins in the human brain are known to be an essential feature of many neurodegenerative diseases, and presenilin-1 (PS1) mutations linked to Alzheimer's disease (AD) have been suggested to alter the misfolded protein response (UPR) due to stress on the endoplasmic reticulum. Moreover, to deal with the stress generated by protein aggregation, cells use a series of protection mechanisms. One of these biological responses to stress involves proteins called molecular chaperones that mediate protein folding, signaling, surveillance, and cell protection. These molecular changes of cellular stress have not only been seen in the neurons of brains from AD patients but also in the peripheral cells of patients with Alzheimer's disease, emphasizing the systemic nature of this pathology. Besides, due to the difficulties in studying dynamic processes in the human brain, peripheral cells are valuable for diagnosis and understanding the molecular mechanisms of AD.METHODS: We cultured fibroblasts from patients affected with familial AD with a presenilin 1 mutation (M146L or A246E) and control subjects, in Minimum Essential Medium Eagle with 15% non-inactivated fetal bovine serum. These cells were characterized by immunodetection and karyotyping. Pathways related to neurodegeneration were analyzed by western blot. Finally, we carried out a proteomic study using mass spectrometry to study the fibroblast´s protein profile from familial AD and controls.
    RESULTS: We identified differences in the expression of proteins related to the autophagic-lysosomal pathway in affected individual´s fibroblasts. We also identified changes in kinases related to hyperphosphorylation of tau protein. We analyzed the protein profile of fibroblasts derived from mass spectrometry and identified groups of proteins related to cellular stress (HSPA8, HSP90AB1, HSPD1, HSPE1) present only in fibroblasts affected with AD and not in controls. From the Western blot analysis, we confirmed the overexpression of HSP90, HSP70, and HSP60.
    CONCLUSION: In summary, our results indicate that fibroblasts from patients with FAD-PS1 show altered pathways associated with cellular stress, autophagy, lysosomes, phosphorylation of tau protein, which shows that fibroblasts can be useful in the search and modeling of pathways related to neurodegeneration, as well as for the identification of early biomarkers related to AD.
    DOI:  https://doi.org/10.1002/alz.053170
  4. Nat Commun. 2022 Feb 01. 13(1): 608
    Pharmacologic IRE1/XBP1s activation promotes systemic adaptive remodeling in obesity.
    Aparajita Madhavan, Bernard P Kok, Bibiana Rius, Julia M D Grandjean, Adekunle Alabi, Verena Albert, Ara Sukiasyan, Evan T Powers, Andrea Galmozzi, Enrique Saez, R Luke Wiseman.
      In obesity, signaling through the IRE1 arm of the unfolded protein response exerts both protective and harmful effects. Overexpression of the IRE1-regulated transcription factor XBP1s in liver or fat protects against obesity-linked metabolic deterioration. However, hyperactivation of IRE1 engages regulated IRE1-dependent decay (RIDD) and TRAF2/JNK pro-inflammatory signaling, which accelerate metabolic dysfunction. These pathologic IRE1-regulated processes have hindered efforts to pharmacologically harness the protective benefits of IRE1/XBP1s signaling in obesity-linked conditions. Here, we report the effects of a XBP1s-selective pharmacological IRE1 activator, IXA4, in diet-induced obese (DIO) mice. IXA4 transiently activates protective IRE1/XBP1s signaling in liver without inducing RIDD or TRAF2/JNK signaling. IXA4 treatment improves systemic glucose metabolism and liver insulin action through IRE1-dependent remodeling of the hepatic transcriptome that reduces glucose production and steatosis. IXA4-stimulated IRE1 activation also enhances pancreatic function. Our findings indicate that systemic, transient activation of IRE1/XBP1s signaling engenders multi-tissue benefits that integrate to mitigate obesity-driven metabolic dysfunction.
    DOI:  https://doi.org/10.1038/s41467-022-28271-2
  5. Alzheimers Dement. 2021 Dec;17 Suppl 3 e052231
    Contribution of ER stress to tau-mediated toxicity.
    Laura J Blair, Marangelie Criado-Marrero.
      BACKGROUND: There are many ways cells in the brain can die. In Alzheimer's disease (AD), the accumulation of tau is linked with cell death, but the major cell death pathway remains to be identified. Prior work has shown that pathogenic tau promotes endoplasmic reticulum (ER) stress and subsequent unfolded protein response (UPR) activation. However, the contribution of ER stress-induced cell death to tau-mediated neurotoxicity is unknown. Interestingly, mice lacking CHOP/Ddit3, an important regulator of ER stress-induced cell death, have been shown to be protected from ER stress induced neuronal loss. We hypothesized that silencing CHOP would prevent tau toxicity through the ER stress pathway and reveal the contribution of tau toxicity that is mediated through this pathway.METHOD: To investigate this, we generated a mouse-targeting CHOP/Ddit3 shRNA AAV9 that also expresses GFP by a separate promoter. We injected shCHOP AAV9 or a shScrambled control AAV9 in the brains of 8-month-old male and female rTg4510 tau transgenic mice and harvested them at 12-months of age, when ER stress is activated, and neuronal loss is occurring in these mice. We performed behavioral studies using the Y-Maze, Open field, and 2-day Radial-Arm water maze task with a reversal paradigm. Unbiased stereology was used to determine neuronal health and effect of CHOP shRNA on CHOP levels was evaluated by immunofluorescence.
    RESULT: AAV9 CHOP shRNA did not alter learning and memory in tau transgenic mice. Evaluation of the tissue revealed a modest, but non-significant increase in neuronal loss from CHOP knock down, while the DG shows a non-significant decrease in neuronal loss. Tissue volume was unchanged in both regions. Very surprising to us, and opposite of what was expected, we found that in these regions of interest the CHOP levels increased in the animal expressing the CHOP.
    CONCLUSION: Overall, this suggests that shCHOP AAV9 does not alter tau-modified behaviors such as learning and memory particularly at this timepoint. Our results also suggest that there may be a compensatory increase in CHOP signaling in neighboring cells, suggesting that the activation of the UPR in the brains of these mice may be a protective mechanism.
    DOI:  https://doi.org/10.1002/alz.052231
  6. Autophagy. 2022 Jan 31. 1-2
    Architecture of the endoplasmic reticulum plays a role in proteostasis.
    Smriti Parashar, Susan Ferro-Novick.
      The endoplasmic reticulum (ER) forms a contiguous network of tubules and sheets. When errors in protein folding occur, misfolded proteins accumulate in the ER. Proteostasis can be restored by ER quality control pathways. Reticulophagy is an ER quality control pathway that uses resident autophagy receptors to link an ER domain to the autophagy machinery. We recently showed that the reticulophagy receptor RTN3L recruits the COPII cargo adaptor SEC24C to target disease-causing mutant proinsulin INS2Akita puncta to the lysosome for degradation. When reticulophagy is disrupted and delivery to the lysosome is blocked, large INS2Akita puncta accumulate in the ER. Photobleach analysis revealed that these puncta behave like liquid condensates and not aggregates, as previously suggested. Other reticulophagy substrates that are segregated into tubules behave like INS2Akita, whereas a substrate of the ER sheets receptor, RETREG1/FAM134B, appears to be less fluid. Large INS2Akita puncta also accumulate when ER sheets are proliferated by the loss of LNPK, or by overproduction of the sheets-producing protein, CKAP4/CLIMP63. Restoring the tubular network by overexpressing reticulons reverses this phenotype. Our findings revealed that fluid-like deleterious cargoes are segregated into tubules to prevent them from expanding and affecting cell health while they are waiting to undergo reticulophagy.
    Keywords:  ER structure; Lunapark; SEC24C; misfolded prohormones and neuropeptides; protein quality control; reticulophagy
    DOI:  https://doi.org/10.1080/15548627.2022.2030175
  7. Nat Neurosci. 2022 Feb 03.
    Large-scale deep multi-layer analysis of Alzheimer's disease brain reveals strong proteomic disease-related changes not observed at the RNA level.
    Erik C B Johnson, E Kathleen Carter, Eric B Dammer, Duc M Duong, Ekaterina S Gerasimov, Yue Liu, Jiaqi Liu, Ranjita Betarbet, Lingyan Ping, Luming Yin, Geidy E Serrano, Thomas G Beach, Junmin Peng, Philip L De Jager, Vahram Haroutunian, Bin Zhang, Chris Gaiteri, David A Bennett, Marla Gearing, Thomas S Wingo, Aliza P Wingo, James J Lah, Allan I Levey, Nicholas T Seyfried.
      The biological processes that are disrupted in the Alzheimer's disease (AD) brain remain incompletely understood. In this study, we analyzed the proteomes of more than 1,000 brain tissues to reveal new AD-related protein co-expression modules that were highly preserved across cohorts and brain regions. Nearly half of the protein co-expression modules, including modules significantly altered in AD, were not observed in RNA networks from the same cohorts and brain regions, highlighting the proteopathic nature of AD. Two such AD-associated modules unique to the proteomic network included a module related to MAPK signaling and metabolism and a module related to the matrisome. The matrisome module was influenced by the APOE ε4 allele but was not related to the rate of cognitive decline after adjustment for neuropathology. By contrast, the MAPK/metabolism module was strongly associated with the rate of cognitive decline. Disease-associated modules unique to the proteome are sources of promising therapeutic targets and biomarkers for AD.
    DOI:  https://doi.org/10.1038/s41593-021-00999-y
  8. Science. 2022 Feb 04. 375(6580): 507
    The protein-folding problem: Not yet solved.
    Peter B Moore, Wayne A Hendrickson, Richard Henderson, Axel T Brunger.
      
    DOI:  https://doi.org/10.1126/science.abn9422
  9. Alzheimers Dement. 2021 Dec;17 Suppl 3 e057689
    Loss of blood-brain barrier properties in association with endoplasmic reticulum stress in vascular cells from in vivo and in vitro models of Alzheimer's disease.
    Carlos Javier Pomilio, Jessica Presa, Nicolás Gabriel González Pérez, Ángeles Vinuesa, Melisa Bentivegna, Amal Gregosa, Kwank Sik Kim, Veronica Galvan, Juan Beauquis, Flavia Eugenia Saravia.
      BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia. Among other histopathological hallmarks, it is characterized by the abnormal accumulation of Amyloid-β (Aβ) peptides. Vascular alterations and blood-brain barrier (BBB) disruption are also evidenced in AD patients, in close association with perivascular amyloid deposits, which are composed mainly of Aβ 1-40. Aβ was linked to endoplasmic reticulum stress (ERS) induction in brain cells. In this study we characterized the progression of vascular alterations in the hippocampus of PDAPP-J20 mice, a validated transgenic model for AD.METHOD: Brain sections from young and old PDAPP-J20 mice were processed for immunohistochemistry against occludin or stained with fluorescent tomato lectin -a vascular marker-. Some mice were previously injected with Evans blue or sodium fluorescein in order to evidence BBB disruption. Also, cerebral microvascular fractions were obtained from old PDAPP-J20 mice and the proteins from these samples were analyzed by mass spectrometry and proteomics analysis. For in vitro assays, human brain microvascular endothelial cells were exposed to fibrillar Aβ1-40. Markers for BBB and ERS were evaluated in these conditions.
    RESULT: We found a significant increment in morphological alterations in vessels from AD mice compared to age-matched controls, mainly in those surrounded by Aβ deposits. In old AD mice, we found an increased BBB permeability, in association with a low signal for the endothelial tight junction protein occludin. Then, we obtained cerebral vascular fractions from AD and control mice and measured the levels of vascular proteins through mass spectrometry and proteomics analysis. We identified 82 proteins whose levels were decreased in AD mice. The enrichment analysis showed that the most represented cellular processes in this sample were translation and protein synthesis. Human brain microvascular endothelial cells exposed to Aβ1-40 showed not only a decrease in the occludin detection with a concomitant reduced transendothelial electrical resistance but an increment in BIP and IRE-1α expression, confirming that Aβ promotes ERS with disruption of the BBB in this model.
    CONCLUSION: Our results suggest that ERS, downregulation of translation and loss of proteostasis in brain vascular cells emerge as mediators for Aβ-induced endothelial alterations during the progression of AD.
    DOI:  https://doi.org/10.1002/alz.057689
  10. Cell Stem Cell. 2022 Feb 03. pii: S1934-5909(22)00007-8. [Epub ahead of print]29(2): 189-208
    iPSC-based disease modeling and drug discovery in cardinal neurodegenerative disorders.
    Hideyuki Okano, Satoru Morimoto.
      It has been 15 years since the birth of human induced pluripotent stem cell (iPSC) technology in 2007, and the scope of its application has been expanding. In addition to the development of cell therapies using iPSC-derived cells, pathological analyses using disease-specific iPSCs and clinical trials to confirm the safety and efficacy of drugs developed using iPSCs are progressing. With the innovation of related technologies, iPSC applications are about to enter a new stage. This review outlines advances in iPSC modeling and therapeutic development for cardinal neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease.
    Keywords:  AD; ALS; Alzheimer’s disease; PD; Parkinson’s disease; amyotrophic lateral sclerosis; disease modeling; drug repositioning; iPSCs; induced pluripotent stem cells; stratification
    DOI:  https://doi.org/10.1016/j.stem.2022.01.007
  11. Alzheimers Dement. 2021 Dec;17 Suppl 3 e053681
    Neuroproteomics of cognitively healthy centenarians in the context of aging and Alzheimer's disease.
    Netherlands Brain Bank
      BACKGROUND: Aging is often accompanied by neurodegenerative diseases such as Alzheimer's disease (AD), and their associated neuropathological hallmarks. Few individuals are able to maintain cognitive health until extreme ages, such as cognitively healthy centenarians, despite displaying substantial pathology in their brains. Here we report on a unique and large single-center proteomics study providing insight into proteome changes occurring with AD and aging. We investigate which mechanisms could be involved in maintaining cognitive health at extreme ages in the presence of pathology.METHOD: We performed quantitative proteomics on middle temporal lobe tissue for a cohort of 61 non-demented and 91 AD individuals across the age-continuum, and 58 centenarians from the 100-plus Study. We performed enrichment analyses for cell-types and GO-terms using multiple approaches (Figure 1).
    RESULT: We identified 3,448 proteins, among which proteins associated with AD Braak stage or age. 472 proteins were associated with Braak stages, independent of age. Cell-type enrichment revealed that with increasing Braak stages, the abundance of astrocytic proteins increased while the abundance of neuronal proteins decreased. Among centenarians we identified 13 proteins that that differ in abundance from AD cases with the same Braak stage (IV). These included ubiquitin, cytoskeletal and synaptic proteins. Additionally, we identified 174 age-related proteins in non-demented controls. Of these, 97 were expressed in centenarians at levels different from those predicted for their age. Cell-type enrichment revealed that the abundance of oligodendrocytic proteins decreased with age, whereas the abundance of astrocytic proteins was increased with age and Braak stage.
    CONCLUSION: Progressive AD stages are associated with increased abundance of astrocytic- and lower abundance of neuronal proteins, while healthy aging is associated with a lower abundance of oligodendrocytic proteins and higher abundance of astrocytic proteins. In this study we identified proteins in the centenarians that deviate in level from prediction based on age. How these proteins act on cognition needs to be investigated further. Centenarian-specific proteins at Braak stage IV may indicate mechanisms protecting against cognitive decline, whereas the centenarian-specific age-related proteins might indicate processes that prevent adverse brain aging.
    DOI:  https://doi.org/10.1002/alz.053681
  12. Free Radic Biol Med. 2022 Jan 31. pii: S0891-5849(22)00041-7. [Epub ahead of print]
    Activation of autophagy attenuates motor deficits and extends lifespan in a C. elegans model of ALS.
    Hui Xu, Congcong Jia, Cheng Cheng, Haifeng Wu, Huaibin Cai, Weidong Le.
      Mutations in Cu/Zn-superoxide dismutase 1 (SOD1) are linked to amyotrophic lateral sclerosis (ALS). Using a line of ALS-related mutant human SOD1 (hSOD1) transgenic Caenorhabditis elegans, we tested the effects of metformin on the progression of ALS-like pathological abnormalities. We found that metformin significantly extended the lifespan, improved motor performance, and enhanced antioxidant activity of mutant worms. We further showed that metformin enhanced expression of lgg-1, daf-16, skn-1 and other genes known to regulate autophagy, longevity and oxidative stress in hSOD1 transgenic worms. Accordingly, overexpression of lgg-1 or daf-16 attenuated the aging and pathological abnormalities of mutant human SOD1 worms, while genetic deletion of lgg-1 or daf-16 abolished the beneficial effects of metformin. Collectively, we demonstrate that metformin protects against mutant SOD1-induced cytotoxicity in part through enhancement of autophagy and extends lifespan through daf-16 pathway. Our findings suggest that metformin could be further explored as a potential therapeutic agent in treating ALS.
    Keywords:  ALS; Autophagy; Lifespan; Metformin; Neuroprotection
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.01.030
  13. Mol Cell Biochem. 2022 Jan 31.
    Endoplasmic reticulum stress induces mitochondrial dysfunction but not mitochondrial unfolded protein response in SH-SY5Y cells.
    Andrea Evinova, Zuzana Hatokova, Zuzana Tatarkova, Maria Brodnanova, Katarina Dibdiakova, Peter Racay.
      In the present study we have shown that treatment of SH-SY5Y cells with either thapsigargin or tunicamycin is associated with a significant decrease in ROUTINE and ATP-coupled mitochondrial respiration as well as a decrease in spare and maximal respiratory capacity. We have also shown that treating cells with either thapsigargin or tunicamycin is associated with significant changes in mitochondrial membrane potential (ΔΨm) generation, which is mainly associated with the reversal of the succinyl-CoA ligase reaction and a decreased activity of complex II. Despite the induction of endoplasmic reticulum (ER) specific unfolded protein response (UPR), as documented by increased expression of HRD1, ER stress did not induce mitochondrial UPR since the expression of both mitochondrial protease LONP1 and mitochondrial chaperone HSP60 was not significantly altered. Inhibition of IRE1α ribonuclease with STF-083010 did not protect the SH-SY5Y cells from ER stress-induced mitochondrial dysfunction. STF-083010 itself had significant impact on both mitochondrial respiration and generation of ΔΨm, which has mainly been associated with the uncoupling of respiratory chain from ATP synthesis.
    Keywords:  Endoplasmic reticulum stress; Mitochondrial dysfunction; Parkinson’s disease; Unfolded protein response
    DOI:  https://doi.org/10.1007/s11010-021-04344-6
  14. Alzheimers Dement. 2021 Dec;17 Suppl 3 e054608
    Modelling the role of APOE4 in blood-brain barrier dysfunctions with isogenic IPSC-derived brain microvascular endothelial cells and pericytes.
    Bill Yunfeng Ding, Richard Daneman, Sean P Palecek, Eric V Shusta.
      BACKGROUND: APOE4 is the strongest genetic risk factor for late-onset Alzheimer's Disease, and is known to affect the function of multiple neuronal and glial cell types. Recent research has suggested that blood-brain barrier (BBB) dysfunction is commonly observed among AD patients. However, it remains unclear whether and how APOE4 directly contributes to blood-brain barrier dysfunction.METHOD: Isogenic iPSC lines with different APOE isoforms were differentiated into brain microvascular endothelial cell-like cells (BMECs) and neural crest-derived pericyte-like cells (PCs). Isogenic BMECs with different APOE isoforms were compared for their tight junction integrity, efflux transporter activity and amyloid clearance capabilities. Isogenic PCs with different APOE isoforms were compared for their APOE secretion levels and amyloid uptake capabilities.
    RESULT: APOE4, APOE3 and APOE2 BMECs exhibited similar levels of tight junction protein expression, efflux transporter activities and trans-endothelial electrical resistance. However, we found that the presence of APOE ε4 protein, when compared with APOE ε2 and APOE ε3, led to reduced BMEC clearance of amyloid in a Transwell model. Compared to APOE3 and APOE2 PCs, APOE4 PCs demonstrated similar levels of APOE secretion, but had lower amyloid uptake capabilities.
    CONCLUSION: Our findings reveal that although APOE4 did not directly affect BMEC barrier properties in our hPSC-derived model, it plays a potentially important role in amyloid clearance by both BMECs and PCs.
    DOI:  https://doi.org/10.1002/alz.054608
This page is being maintained by Thomas Krichel. It was last updated on 2022‒02‒06 at 17:47:06.