Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene-dose-sensitive AD-suppressor in human brain

Alic, I.; Goh, P. A.; Murray, A.; Portelius, E.; Gkanatsiou, E.; Gough, G.; Mok, K. Y.; Koschut, D.; Brunmeir, R.; Yeap, Y. J.; O'Brien, N. L.; Groet, J.; Shao, X.; Havlicek, S.; Dunn, N. R.; Kvartsberg, H.; Brinkmalm, G.; Hithersay, R.; Startin, C.; Hamburg, S.; Phillips, M.; Pervushin, K.; Turmaine, M.; Wallon, D.; Rovelet-Lecrux, A.; Soininen, H.; Volpi, E.; Martin, J. E.; Foo, J. N.; Becker, D. L.; Rostagno, A.; Ghiso, J.; Krsnik, Z.; Simic, G.; Kostovic, I.; Mitrecic, D.; LonDownS Consortium,; Francis, P. T.; Blennow, K.; Strydom, A.; Hardy, J.; Zetterberg, H.; Nizetic, D.

doi:10.1101/2020.01.29.918037

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bioRxiv · 10.1101/2020.01.29.918037

Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene-dose-sensitive AD-suppressor in human brain

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Abstract

A population of >6 million people worldwide at high risk of Alzheimers disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of {beta}-amyloid-(A{beta})-precursor-protein gene. We report AD-like pathology in cerebral organoids grown in vitro from non-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar A{beta} deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss. Presence/absence of AD-like pathology was donor-specific (reproducible between individual organoids/iPSC lines/experiments). Pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome-21-gene BACE2, but prevented by combined chemical {beta} and {gamma}-secretase inhibition. We found that T21-organoids secrete increased proportions of A{beta}-preventing (A{beta}1-19) and A{beta}-degradation products (A{beta}1-20 and A{beta}1-34). We show these profiles mirror in cerebrospinal fluid of people with DS. We demonstrate that this protective mechanism is mediated by BACE2-trisomy and cross-inhibited by clinically trialled BACE1-inhibitors. Combined, our data prove the physiological role of BACE2 as a dose-sensitive AD-suppressor gene, potentially explaining the dementia delay in [~]30% of people with DS. We also show that DS cerebral organoids could be explored as pre-morbid AD-risk population detector and a system for hypothesis-free drug screens as well as identification of natural suppressor genes for neurodegenerative diseases.

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Alic, I., Goh, P. A., Murray, A., Portelius, E., Gkanatsiou, E., Gough, G., Mok, K. Y., Koschut, D., Brunmeir, R., Yeap, Y. J., O'Brien, N. L., Groet, J., Shao, X., Havlicek, S., Dunn, N. R., Kvartsberg, H., Brinkmalm, G., Hithersay, R., Startin, C., Hamburg, S., Phillips, M., Pervushin, K., Turmaine, M., Wallon, D., Rovelet-Lecrux, A., Soininen, H., Volpi, E., Martin, J. E., Foo, J. N., Becker, D. L., Rostagno, A., Ghiso, J., Krsnik, Z., Simic, G., Kostovic, I., Mitrecic, D., LonDownS Consortium,, Francis, P. T., Blennow, K., Strydom, A., Hardy, J., Zetterberg, H., Nizetic, D.. 2020-01-31. Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene-dose-sensitive AD-suppressor in human brain. https://doi.org/10.1101/2020.01.29.918037

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