Targeting the Endosome for Alzheimer's Drug Discovery
Principal Investigator
Project Goals
Apolipoprotein E4 (ApoE4) status is the primary and biomedically most important risk factor for Alzheimer’s disease (AD). We have found a novel mechanism by which ApoE4 weakens synaptic strength in neurons, which led us to identify a promising novel endosomal drug target. This proposal aims to establish the necessary mechanistic and infrastructural baseline to screen for modifiers of endosomal function and for discovering novel potential methods to target the endosome in vitro and in vivo. This is necessary for the evolution of a conceptually novel and therapeutically effective preventive approach to AD, at least for the majority of patients carrying the ApoE4 allele.
Project Summary
Apolipoprotein E4 status is the primary and biomedically most important risk factor for Alzheimer’s disease. We have found that upon internalization by neurons, ApoE4 leads to an endosomal vesicular trafficking defect that sequesters ApoE receptors and neurotransmitter receptors in the endosome, thereby weakening synaptic strength. Based on available structural and functional data, we predicted and experimentally demonstrated that it is possible to modify ApoE structure as well as endosomal function to restore normal ApoE recycling, revealing this approach as a promising novel drug target.
Thus, this project investigates the endosome as a novel and largely unexplored target for drug development. We have presented ample experimental evidence for the validity of the target and the feasibility of developing drugs targeting this endosomal protein. Successful completion of the project would establish a novel therapeutic approach to AD that has the potential to abolish the ApoE4 risk for developing the most frequent late-onset form of the disease.
Publications
Mohammad I. K. Hamad, Solieman Daoud, Petya Petrova, Obada Rabaya, Abdalrahim Jbara, Nesrine Melliti, Sarah Stichmann, Gebhard Reiss, Joachim Herz, Eckart Förster.
Biolistic transfection and expression analysis of acute cortical slices.
J Neurosci Methods. May 1;337:108666 (2020). doi: 10.1016/j.jneumeth.2020.108666.
Epub 2020 Feb 28. PMID: 32119875; PMCID: PMC7125026.
Laurent Calvier, Guillaume Demuth, Navid Manouchehri, Connie Wong, Anastasia Sacharidou,
Chieko Mineo, Philip W. Shaul, Nancy L Monson, Maria Z Kounnas, Olaf Stüve, Joachim Herz.
Reelin Depletion Protects Against Autoimmune Encephalitis by Decreasing Vascular Adhesion of Leukocytes.
Sci Transl Med. Aug 12;12(556):eaay7675 (2020). doi: 10.1126/scitranslmed.aay7675. PMID: 32801146; PMCID: PMC7860587.
Laurent Calvier, Xunde Xian, Richard Lee, Anastasia Sacharidou, Chieko Mineo, Philip W. Shaul, Maria Z. Kounnas, Shirling Tsai, Joachim Herz.
Reelin Depletion Protects Against Atherosclerosis by Decreasing Vascular Adhesion of Leukocytes.
Arterioscler Thromb Vasc Biol. Feb 25:ATVBAHA121316000 (2021). doi: 10.1161/ATVBAHA.121.316000. Epub ahead of print. PMID: 33626909; PMCID: PMC7990715.
Mohammad I. K. Hamad, Abdairahim Jbara, Obada Rabaya, Petya Petrova, Solieman Daoud, Nesrine Melliti, Maurice Meseke, David Lutz, Elisabeth Petrasch-Parwez, Jan Claudius Schwitalla, Melanie D. Mark, Stefan Herlitze, Gebhard Reiss, Joachim Herz, Eckart Förster.
Reelin signaling modulates GABAB receptor function in the neocortex.
J Neurochem. Mar;156(5):589-603 (2021). doi: 10.1111/jnc.14990. Epub 2020 Mar 13. PMID: 32083308; PMCID: PMC7442713.
Murat Durakoglugil, Catherine R. Wasser, Connie H. Wong, Theresa Pohlkamp, Xunde Xian, Courtney Lane-Donovan, Katja Fritschle, Lea Naestle, Joachim Herz.
Reelin Regulates Neuronal Excitability through Striatal-Enriched Protein Tyrosine Phosphatase (STEP61) and Calcium Permeable AMPARs in an NMDAR-Dependent Manner. J Neurosci. 2021 Sep 1;41(35):7340-7349. doi: 10.1523/JNEUROSCI.0388-21.2021. Epub 2021 Jul 21. PMID: 34290083; PMCID: PMC8412985.
Laurent Calvier, Navid Manouchehri. Anastasia Sacharidou, Chieko Mineo, Philip W. Shaul, David Y. Hui, Maria Z Kounnas, Olaf Stüve, Joachim Herz.
Apolipoprotein E receptor 2 deficiency decreases endothelial adhesion of monocytes and protects against autoimmune encephalomyelitis. Sci Immunol. 2021 Aug 27;6(62):eabd0931. doi: 10.1126/sciimmunol.abd0931. PMID: 34452924; PMCID: PMC8627794.
Mohammad K. Hamad, Petya Petrova, Solieman Daoud, Obada Rabaya, Abdairahim Jbara, Nesrine Melliti, Jennifer Leifeld, Igor Jakovčevski, Gebhard Reiss, Joachim Herz,, Eckart Förster.
Reelin restricts dendritic growth of interneurons in the neocortex. Development.
Sep 1;148(17):dev199718 (2021). doi: 10.1242/dev.199718. Epub 2021 Sep 6. PMID: 34414407; PMCID: PMC8451942.
Haiyan Chu, Anastasia Sacharidou, An Nguyen, Chun Li, Ken L. Chambliss, Jane E. Salmon, Yu-Min Shen, Julie Lo, Gustavo W. Leone, Joachim Herz, David Y. Hui, Denise K. Marciano, Vikki M. Abrahams, Bryony V. Natale, Alina P. Montalbano, Xue Xiao, Lin Xu, David R. Natale, Philip W. Shaul, Chieko Mineo.
Protein Phosphatase 2A Activation Via ApoER2 in Trophoblasts Drives Preeclampsia in a Mouse Model of the Antiphospholipid Syndrome.
Circ Res. 2021 Sep 17;129(7):735-750. doi: 10.1161/CIRCRESAHA.120.318941. Epub 2021 Aug 18. PMID: 34404233; PMCID: PMC8448973.
Ye-Ji Bang, Zehan Hu, Yun Li, Sureka Gattu, Kelly A Ruhn, Pithyi Raj, Joachim Herz, and Lora V. Hooper,
Serum amyloid A delivers retinol to intestinal myeloid cells to promote adaptive immunity.
Science. 2021 Sep 17;373(6561):eabf9232. doi: 10.1126/science.abf9232. Epub 2021 Sep 17. PMID: 34529485; PMCID: PMC8532503.
Austin T. Marckx, Katja E. Fritschle, Laurent Calvier, Joachim Herz.
Reelin changes hippocampal learning in aging and Alzheimer's disease.
Behav Brain Res. 2021 Sep 24;414:113482. doi: 10.1016/j.bbr.2021.113482.
Epub 2021 Jul 29. PMID: 34333070; PMCID: PMC8483237.
Theresa Pohlkamp, Xunde Xian, Connie H. Wong, Murat S. Durakoglugil, Gordon Chandler Werthmann, Takaomi C. Saido, Bret M. Evers, Charles L. White 3rd, Jade Connor, Robert E. Hammer, Joachim Herz.
NHE6 depletion corrects ApoE4-mediated synaptic impairments and reduces amyloid plaque load. Elife. Oct 7;10:e72034 (2021). doi: 10.7554/eLife.72034. PMID: 34617884; PMCID: PMC8547963.
Sara Awan, Magalie Lambert, Ali Imtiaz, Fabien Alpy, Catherine Tomasetto, Mustapha Oulad-Abdelghani, Christine Schaeffer, Chloé Moritz, Diane Julien-David, Souad Najib, Laurent O. Martinez, Rachel L. Matz, Xavier Collet, Roberto Silva-Rojas, Johann Böhm, Joachim Herz, Jérôme Terrand, Philippe Boucher. Wnt5a Promotes Lysosomal Cholesterol Egress and Protects Against Atherosclerosis.
Circ Res. Jan 21;130(2):184-199 (2022). doi: 10.1161/CIRCRESAHA.121.318881. Epub 2021 Dec 10. PMID: 34886684; PMCID: PMC8776607.
Laurent Calvier, Joachim Herz, Georg Hansmann.
Interplay of Low-Density Lipoprotein Receptors, LRPs, and Lipoproteins in Pulmonary Hypertension.
JACC Basic Transl Sci. 2022 Feb 28;7(2):164-180. doi: 10.1016/j.jacbts.2021.09.011. PMID: 35257044; PMCID: PMC8897182.
First published on: August 31, 2016
Last modified on: April 29, 2024