Neuroinflammation in neurodegenerative disease

The resident macrophages of the brain parenchyma – microglia – are critical in maintaining brain health, and when they are dysfunctional, diseases from dementias to neurocognitive disorders can result. Several of the genes associated with Alzheimer’s disease are specifically expressed in microglia rather than other brain cell types, and progression of the disease is characterised by failure of tissue homeostasis by microglia, with accumulation of misfolded amyloid beta and tau proteins.

We have used our iPSC models to examine the role of microglia in neuroinflammation, particularly in the context of Alzheimer’s, Parkinson’s and ALS. The following publications illustrate some of the results of this work:

C9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9. Vahsen BF, Nalluru S, Morgan GR, Farrimond L, Carroll E, Xu Y, Cramb KML, Amein B, Scaber J, Katsikoudi A, Candalija A, Carcolé M, Dafinca R, Isaacs AM, Wade-Martins R, Gray E, Turner MR, Cowley SA, Talbot K. Nat Commun. 2023 Sep 22;14(1):5898.

Type I interferon receptor (IFNAR2) deficiency reveals Zika virus cytopathicity in human macrophages and microglia. Hanrath AT, Hatton CF, Gothe F, Browne C, Vowles J, Leary P, Cockell SJ, Cowley SA, James WS, Hambleton S, Duncan CJA. Front Immunol. 2022 Nov 11;13:1035532.

Single-cell transcriptomics defines an improved, validated monoculture protocol for differentiation of human iPSC to microglia. Washer SJ, Perez-Alcantara M, Chen Y, Steer J, James WS, Trynka G, Bassett AR, Cowley SA. Sci Rep. 2022 Nov 14;12(1):19454.

Lipopolysaccharide distinctively alters human microglia transcriptomes to resemble microglia from Alzheimer’s disease mouse models. Monzón-Sandoval J, Burlacu E, Agarwal D, Handel AE, Wei L, Davis J, Cowley SA, Cader MZ, Webber C. Dis Model Mech. 2022 Oct 1;15(10):dmm049349.

Human iPSC co-culture model to investigate the interaction between microglia and motor neurons. Vahsen BF, Gray E, Candalija A, Cramb KML, Scaber J, Dafinca R, Katsikoudi A, Xu Y, Farrimond L, Wade-Martins R, James WS, Turner MR, Cowley SA, Talbot K. Sci Rep. 2022 Jul 23;12(1):12606.

Pathogenic LRRK2 regulates centrosome cohesion via Rab10/RILPL1-mediated CDK5RAP2 displacement. Fdez E, Madero-Pérez J, Lara Ordóñez AJ, Naaldijk Y, Fasiczka R, Aiastui A, Ruiz-Martínez J, López de Munain A, Cowley SA, Wade-Martins R, Hilfiker S. iScience. 2022 May 30;25(6):104476.

Microglia integration into human midbrain organoids leads to increased neuronal maturation and functionality. Sabate-Soler S, Nickels SL, Saraiva C, Berger E, Dubonyte U, Barmpa K, Lan YJ, Kouno T, Jarazo J, Robertson G, Sharif J, Koseki H, Thome C, Shin JW, Cowley SA, Schwamborn JC. Glia. 2022 Jul;70(7):1267-1288.

iPSC-Derived Microglia as a Model to Study Inflammation in Idiopathic Parkinson’s Disease. Badanjak K, Mulica P, Smajic S, Delcambre S, Tranchevent LC, Diederich N, Rauen T, Schwamborn JC, Glaab E, Cowley SA, Antony PMA, Pereira SL, Venegas C, Grünewald A. Front Cell Dev Biol. 2021 Nov 5;9:740758.

In vitro Quantitative Imaging Assay for Phagocytosis of Dead Neuroblastoma Cells by iPSC-Macrophages. Hall-Roberts H, Di Daniel E, James WS, Davis JB, Cowley SA. J Vis Exp. 2021 Feb 14;(168).

Alzheimer’s Risk Gene TREM2 Determines Functional Properties of New Type of Human iPSC-Derived Microglia. Reich M, Paris I, Ebeling M, Dahm N, Schweitzer C, Reinhardt D, Schmucki R, Prasad M, Köchl F, Leist M, Cowley SA, Zhang JD, Patsch C, Gutbier S, Britschgi M. Front Immunol. 2021 Feb 3;11:617860.

TREM2 Alzheimer’s variant R47H causes similar transcriptional dysregulation to knockout, yet only subtle functional phenotypes in human iPSC-derived macrophages. Hall-Roberts H, Agarwal D, Obst J, Smith TB, Monzón-Sandoval J, Di Daniel E, Webber C, James WS, Mead E, Davis JB, Cowley SA. Alzheimers Res Ther. 2020 Nov 16;12(1):151

LRRK2 Is Recruited to Phagosomes and Co-recruits RAB8 and RAB10 in Human Pluripotent Stem Cell-Derived Macrophages. Lee H, Flynn R, Sharma I, Haberman E, Carling PJ, Nicholls FJ, Stegmann M, Vowles J, Haenseler W, Wade-Martins R, James WS, Cowley SA. Stem Cell Reports. 2020 May 12;14(5):940-955.

LRRK2 is a negative regulator of Mycobacterium tuberculosis phagosome maturation in macrophages. Härtlova, A., Herbst, S., Peltier, J., Rodgers, A., Bilkei-Gorzo, O., Fearns, A., Dill, B. D., Lee, H., Flynn, R., Cowley, S. A., Davies, P., Lewis, P. A., Ganley, I. G., Martinez, J., Alessi, D. R., Reith, A. D., Trost, M., and Gutierrez, M. G. EMBO J. 2018 Jun 15;37(12)

Haenseler, W., Zambon, F., Lee, H., Vowles, J., Rinaldi, F., Duggal, G., Houlden, H., Gwinn, K., Wray, S., Luk, K. C., Wade-Martins, R., James, W. S., and Cowley, S. A. (2017). Excess α-synuclein compromises phagocytosis in iPSC-derived macrophages. Scientific reports7(1).

Haenseler, W., Sansom, S. N., Buchrieser, J., Newey, S. E., Moore, C. S., Nicholls, F. J., Chintawar, S., Schnell, C., Antel, J. P., Allen, N. D., Cader, M. Z., Wade-Martins, R., James, W. S., and Cowley, S. A. (2017). A highly efficient human pluripotent stem cell microglia model displays a Neuronal-Co-culture-Specific expression profile and inflammatory response. Stem cell reports8(6):1727-1742.