Latest Publication:

APOE and Alzheimer’s Disease: Pathologic Clues from Transgenic Drosophila melanogaster.

Mohammad Haddadi, Mehrnaz Haghi, Niloofar Rezaei, Zahra Kiani, Taha Akkülah, Arzu Celik

Archives of Gerontology and Geriatrics; in press https://doi.org/10.1016/j.archger.2024.105420

Alzheimer's disease (AD) is one of the most common forms of neurodegenerative diseases. Apolipoprotein E4 (ApoE4) is the main genetic risk factor in the development of late-onset AD. However, the exact mechanism underlying ApoE4-mediated neurodegeneration remains unclear. We utilized Drosophila melanogaster to examine the neurotoxic effects of various human APOE isoforms when expressed specifically in glial and neural cells. We assessed impacts on mitochondrial dynamics, ER stress, lipid metabolism, and bio-metal ion concentrations in the central nervous system (CNS) of the transgenic flies. Dachshund antibody staining revealed a reduction in the number of Kenyon cells. Behavioral investigations including ethanol tolerance and learning and memory performance demonstrated neuronal dysfunction in APOE4-expressing larvae and adult flies. Transcription level of marf and drp-1 were found to be elevated in APOE4 flies, while atf4, atf6, and xbp-1s showed down regulation. Enhanced concentrations of triglyceride and cholesterol in the CNS were observed in APOE4 transgenic flies, with especially pronounced effects upon glial-specific expression of the gene. Spectrophotometry of brain homogenate revealed enhanced Fe++ and Zn++ ion levels in conjunction with diminished Cu++ levels upon APOE4 expression. To explore therapeutic strategies, we subjected the flies to heat-shock treatment, aiming to activate heat-shock proteins (HSPs) and assess their potential to mitigate the neurotoxic effects of APOE isoforms. The results showed potential therapeutic benefits for APOE4-expressing flies, hinting at an ability to attenuate memory deterioration. Overall, our findings suggest that APOE4 can alter lipid metabolism, bio metal ion homeostasis, and disrupt the harmonious fission-fusion balance of neuronal and glial mitochondria, ultimately inducing ER stress. These alterations mirror the main clinical manifestations of AD in patients. Therefore, our work underscores the suitability of Drosophila as a fertile model for probing the pathological roles of APOE and furthering our understanding of diverse isoform-specific functions.

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Selected Publications:

  • Bekpen C, Baker C, Hebert MD, Şahin HB, Johnson ME, Çelik A, Mullikin J, NISC Sequencing Program, and Eichler E, Functional characterization of the Morpheus gene family, bioRxiv preprint posted March 12, 2017; doi: http://dx.doi.org/10.1101/116087
  • Çevrim BÇ, Mika K, Özturan G, Kahraman A, Vulstreke V, Callaerts P, and Çelik A (2022) The cell adhesion molecule Unzipped mediates neuron-neuron and neuron-glia interactions to control mushroom body development. isubmitted Cell and Tissue Research
  • Khoshbakht S, Beheshtian M, Fattahi Z, Bazazzadegan Z, Parsimehr E, Fadaee M, Vazehan R, Zonooz MF, Abolhassani A, Makvand M, Kariminejad A, Çelik, A, Kahrizi, K., and H. Najmabadi (2021) CEP104 and CEP290; genes with ciliary functions cause intellectual disability in multiple Iranian families. Archives of Iranian Medicine, 24(5):364-373, doi: 10.34172/aim.2021.53
  • Şahin HB, Sayın S, Holder M, Buğra K, and Çelik A (2020) Salt Inducible Kinases as Novel Notch Interactors in the Developing Drosophila Retina. PLoS One, 15(6): e0234744, doi: 10.1371/journal.pone.0234744
  • Terzioğlu Kara E, Kıral FR, Öztürk Çolak A, and Çelik A (2020) Generation and characterization of inner photoreceptor‐specific enhancer‐trap lines using a novel piggyBac‐Gal4 element in Drosophila. Archives of Insect Biochemistry and Physiology 104(2):e21675
  • Dereli Eke E, Arga KY, Dikicioglu D, Eraslan S, Erkol E, Çelik A, Kirdar B, and Di Camillo B (2019) Identification of Novel Components of Target-of-Rapamycin Signaling Pathway by Network-Based Multi-Omics Integrative Analysis OMICS: A Journal of Integrative Biology 23(5):274-284. https://doi.org/10.1089/omi.2019.0021
  • Kazeminasab S, Taşkıran II, Fattahi Z, Bazzazzadegan N, Hosseini M, Rahimi M, Olaad Nabi M, Haddadi M, Çelik A, Ropers HH, Najmabadi H, and K Kahrizi K (2018) CNKSR1 gene defect can cause syndromic autosomal recessive intellectual disability. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 177(8):691-699. doi: 10.1002/ajmg.b.32648
  • Fattahi Z, Sheikh T, Musante L, Rasheed M, Taşkıran II, Harripaul R, Hu H, Kazeminasab S, Alam MR, Hosseini M, Larti F, Ghaderi Z, Çelik A, Ayub M, Ansar M, Haddadi M, Wienker TF, Ropers HH, Kahrizi K, Vincent JB, and H Najmabadi (2018) Biallelic missense variants in ZBTB11 can cause intellectual disability in human. Human Molecular Genetics 27(18):3177-3188. doi: 10.1093/hmg/ddy220.
  • Köstler S, Alaybeyoğlu B, Weichenberger CX, and Çelik A (2015) FlyOde – a platform for community curation and interactive visualization of dynamic gene regulatory networks in Drosophila eye development. F1000Research 4:1484-9.
  • Potier D, Davie K, Hulselmans G, Sanchez MN, Haagen L, Huynh-Thu VA, Koldere D, Çelik A, Geurts P, Christiaens V, and Aerts S (2014) Mapping gene regulatory networks in Drosophila eye development by large-scale transcriptome perturbations and motif inference. Cell Reports 9:1-14.
  • Mishra AK, Tsachaki M, Rister J, Shy D, Ng J, Çelik A, and Sprecher SG (2013) Binary cell fate decisions and fate transformation in the Drosophila larval eyeila. PLoS Genetics 9(12):e1004027.
  • Li X, Erclik T, Chen Z, Venkatesh S, Morante J, Çelik A, and Desplan C, (2013) Temporal specification of neuroblasts controls neuronal diversity in the Drosophila medulla. Nature 498(7455):456-62.
  • Vasiliauskas D, Mazzoni EO, Sprecher SG, Johnston RJ Jr, Lidder P, Vogt N, Çelik A, and Desplan C (2011) Feedback from Rhodopsin controls Rhodopsin exclusion in Drosophila R8 photoreceptors. Nature 479(7371):108-12.
  • Mazzoni EO, Çelik A, Wernet MF, Vasiliauskas D, Cook TA, Johnston RJ, Pichaud F, and Desplan C (2008) Iroquois-Complex genes induce co-expression of visual pigments in Drosophila. PLoS Biology 6(4):e9.
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    Primer:
    Stavenga DG, and Arikawa K (2008) One Rhodopsin per Photoreceptor: Iro-C Genes Break the Rule. PLoS Biology 6(4):e115.
  • Wernet MF, Çelik A, Mikeladze-Dvali T, and Desplan C (2007) Generation of uniform fly retinas. Current Biology 17(23):r1002-3.
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  • Wernet MF*, Mazzoni EO*, Çelik A*, Duncan DM, Duncan I, and Desplan C (2006) Stochastic spineless expression creates the retinal mosaic for colour vision. Nature 440(7081):174-180. *equal contribution
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    Featured in
    Faculty1000 ("9") and
    Hummel T, and Klaembt C (2006) Eye development: random precision in color vision. Current Biology 16(10):R361-R363.




REVIEWS

  • Şahin HB, and Çelik A (2013) Drosophila eye development and photoreceptor specification eLS, John Wiley & Sons, Ltd: Chichester. DOI:10.1002/9780470015902.a0001147.pub2.
  • Morante J, Desplan C, and Çelik A (2007) Generating patterned arrays of photoreceptors. Current Opinion in Developmental Genetics 17(4):314-9. Review
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  • Fuss S, Çelik A, and Desplan C (2007) Olfactory identity kicked up a Notch. Nature Neuroscience 10(2):138-140. News&Views
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  • Mazzoni EO, Desplan C, and Çelik A (2004) 'One receptor' rules in sensory neurons. Developmental Neuroscience 26(5-6):388-95. Review
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BOOK CONTRIBUTIONS

  • A. Çelik ve Wernet, M.F.W., Editors, "Decoding Neural Circuit Structure and Function: Cellular Dissection Using Genetic Model Organisms," Springer Verlag GmbH DOI 10.1007/978-3-319-57363-2
 ISBN 978-3-319-57362-5
 ISBN 978-3-319-57363-2 (eBook)
 15.07.2017.
  • Scott F. Gilbert, "Gelişim Biyolojisi, Bölüm 7, Amfibiler ve Balıklar: Erken gelişim ve eksen oluşumu," Çeviri: Arzu Çelik, 2013, Nobel Kitapevi.

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