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

Alić, 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, Ž., Šimić, G., Kostović, I., Mitrečić, D., LonDownS Consortium, Francis, P.T., Blennow, K., Strydom, A., Hardy, J., Zetterberg, H. and Nižetić, D. 2021. Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain. Molecular Psychiatry. 26, p. 5766–5788. https://doi.org/10.1038/s41380-020-0806-5

TitlePatient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain
TypeJournal article
AuthorsAlić, 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, Ž., Šimić, G., Kostović, I., Mitrečić, D., LonDownS Consortium, Francis, P.T., Blennow, K., Strydom, A., Hardy, J., Zetterberg, H. and Nižetić, D.
Abstract

A population of >6 million people worldwide at high risk of Alzheimer’s 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 β-amyloid-(Aβ)-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 Aβ 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 β and γ-secretase inhibition. We found that T21-organoids secrete increased proportions of Aβ-preventing (Aβ1-19) and Aβ-degradation products (Aβ1-20 and Aβ1-34). 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.

Keywords β-secretase
cerebral organoid
BACE2
BACE-inhibitor
trisomy 21
JournalMolecular Psychiatry
Journal citation26, p. 5766–5788
ISSN1359-4184
Year2021
PublisherSpringer
Publisher's version
License
CC BY 4.0
File Access Level
Open (open metadata and files)
Digital Object Identifier (DOI)https://doi.org/10.1038/s41380-020-0806-5
Web address (URL)https://www.nature.com/articles/s41380-020-0806-5
Publication dates
Published online10 Jul 2020
Published in print2021

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Suliman, S.G., Stanik, J., McCulloch, L.J., Wilson, N., Edghill, E.L., Misovicova, N., Gasperikova, D., Sandrikova, V., Elliott, K.S., Barak, L., Ellard, S., Volpi, E.V., Klimes, I. and Gloyn, A.L. 2009. Severe insulin resistance and intrauterine growth deficiency associated with haploin sufficiency for INSR and CHN2: new insights into synergistic pathways involved in growth and metabolism. Diabetes. 58 (12), pp. 2954-2961. https://doi.org/10.2337/db09-0787

FISH glossary: an overview of the fluorescence in situ hybridization technique.
Volpi, E.V. and Bridger, J.M. 2008. FISH glossary: an overview of the fluorescence in situ hybridization technique. BioTechniques. 45 (4), pp. 385-409. https://doi.org/10.2144/000112811

Endothelial Nox2 overexpression potentiates vascular oxidative stress and hemodynamic response to angiotensin II: studies in endothelial-targeted Nox2 transgenic mice.
Bendall, J.K., Rinze, R., Adlam, D., Tatham, A.L., de Bono, J., Wilson, N., Volpi, E. and Channon, K.M. 2007. Endothelial Nox2 overexpression potentiates vascular oxidative stress and hemodynamic response to angiotensin II: studies in endothelial-targeted Nox2 transgenic mice. Circulation Research. 100, pp. 1016-1025. https://doi.org/10.1161/01.res.0000263381.83835.7b

Replication profile of PCDH11X and PCDH11Y, a gene pair located in the non-pseudoautosomal homologous region Xq21.3/Yp11.2.
Wilson, N.D., Ross, L.J., Close, J., Mott, R., Crow, T.J. and Volpi, E.V. 2007. Replication profile of PCDH11X and PCDH11Y, a gene pair located in the non-pseudoautosomal homologous region Xq21.3/Yp11.2. Chromosome Research. 15, pp. 485-498. https://doi.org/10.1007/s10577-007-1153-y

Search for neuroblastoma loci: characterization of tumor cell lines that could facilitate their positional cloning.
Romani, M., Muresu, R., Volpi, E.V., Rozzo, C., Marchi, J.M. and Casciano, I. 2007. Search for neuroblastoma loci: characterization of tumor cell lines that could facilitate their positional cloning. Journal of Neuro-oncology . 31, pp. 41-47. https://doi.org/10.1023/a:1005725112688

PCDH11 is X/Y homologous in Homo sapiens but not in Gorilla gorilla and Pan troglodytes.
Wilson, N.D., Ross, L.J., Crow, T.J. and Volpi, E.V. 2006. PCDH11 is X/Y homologous in Homo sapiens but not in Gorilla gorilla and Pan troglodytes. Cytogenetic and Genome Research. 114, pp. 137-139. https://doi.org/10.1159/000093329

The leukocyte receptor complex in chicken is characterized by massive expansion and diversification of immunoglobulin-like Loci.
Laun, K., Coggill, P., Palmer, S., Sims, S., Ning, Z., Ragoussis, J., Volpi, E., Wilson, N., Beck, S., Ziegler, A. and Volz, A. 2006. The leukocyte receptor complex in chicken is characterized by massive expansion and diversification of immunoglobulin-like Loci. PLoS Genetics. 2 (5) e73. https://doi.org/10.1371/journal.pgen.0020073

An interstitial deletion-insertion involving chromosomes 2p25.3 and Xq27.1, near SOX3, causes X-linked recessive hypoparathyroidism.
Bowl, M.R., Nesbit, M.A., Harding, B., Levy, E., Jefferson, A., Volpi, E.V., Rizzoti, K., Lovell-Badge, R., Schlessinger, D., Whyte, M.P. and Thakker, R.V. 2005. An interstitial deletion-insertion involving chromosomes 2p25.3 and Xq27.1, near SOX3, causes X-linked recessive hypoparathyroidism. Journal of Clinical Investigation. 115 (10), pp. 2822-2831. https://doi.org/10.1172/jci24156

Unexpected complexity in the haplotypes of commonly used inbred strains of laboratory mice
Yalcin, B., Fullerton, J., Miller, S., Keays, D.A., Brady, S., Bhomra, A., Jefferson, A., Volpi, E., Copley, R.R., Flint, J. and Mott, R. 2004. Unexpected complexity in the haplotypes of commonly used inbred strains of laboratory mice. Proceedings of the National Academy of Sciences of the United States of America. https://doi.org/10.1073/pnas.0401189101

Mapping of three translocation breakpoints associated with orofacial clefting within 6p24 and identification of new transcripts within the region
Davies, S.J., Wise, C., Venkatesh, B., Mirza, G., Jefferson, A., Volpi, E.V. and Ragoussis, J. 2004. Mapping of three translocation breakpoints associated with orofacial clefting within 6p24 and identification of new transcripts within the region. Cytogenetic and Genome Research. 105, pp. 47-53. https://doi.org/10.1159/000078008

Cohesion, but not too close
Volpi, E.V., Sheer, D. and Uhlmann, F. 2001. Cohesion, but not too close. Current Biology. 11 (10), p. R378. https://doi.org/10.1016/s0960-9822(01)00212-3

Large-scale chromatin organization of the major histocompatibility complex and other regions of human chromosome 6 and its response to interferon in interphase nuclei.
Volpi, E.V., Chevret, E., Jones, T., Vatcheva, R., Williamson, J., Beck, S., Campbell, R.D., Goldsworthy, M., Powis, S.H., Ragoussis, J., Trowsdale, J. and Sheer, D. 2000. Large-scale chromatin organization of the major histocompatibility complex and other regions of human chromosome 6 and its response to interferon in interphase nuclei. Journal of Cell Science. 113 (Pt 9), pp. 1565-1576. https://doi.org/10.1242/jcs.113.9.1565

Mini review: form and function in the human interphase chromosome
Chevret, E., Volpi, E.V. and Sheer, D. 2000. Mini review: form and function in the human interphase chromosome. Cytogenetics and Cell Genetics. 90 (1-2), pp. 13-21. https://doi.org/10.1159/000015654

Nucleotide sequence and chromosomal mapping of the 5S rDNA repeat of the crustacean Proasellus coxalis.
Pelliccia, F., Barzotti, R., Volpi, E.V., Bucciarelli, E. and Rocchi, A. 1998. Nucleotide sequence and chromosomal mapping of the 5S rDNA repeat of the crustacean Proasellus coxalis. Genome. 41 (1), pp. 129-123. https://doi.org/10.1139/g97-110

Numerical abnormalities of chromosomes 1 and 10 in endometrial adenocarcinoma: fluorescence in situ hybridization analysis of 23 archival paraffin-embedded samples.
Muresu, R., Cossu, A., Scarpa, A.M., Volpi, E.V., Rocca, P.C., Pintus, A., Tibiletti, M.G., Tanda, F., Pirastu, M. and Massarelli, G. 1998. Numerical abnormalities of chromosomes 1 and 10 in endometrial adenocarcinoma: fluorescence in situ hybridization analysis of 23 archival paraffin-embedded samples. Cancer Genetics and Cytogenetics. 107 (1), pp. 37-42. https://doi.org/10.1016/s0165-4608(98)00059-4

An integrated physical and genetic map spanning chromosome band 10q24.
Gray, I.C., Fallowfield, J., Ford, S., Nobile, C., Volpi, E.V. and Spurr, N.K. 1997. An integrated physical and genetic map spanning chromosome band 10q24. Genomics. 43 (1), pp. 85-88. https://doi.org/10.1006/geno.1997.4809

Detailed physical analysis of a 1.5-megabase YAC contig containing the MXI1 and ADRA2A genes.
Manca, A., Volpi, E.V., Laficara, F., Muresu, R., Gray, I.C., Spurr, N.K. and Nobile, C. 1997. Detailed physical analysis of a 1.5-megabase YAC contig containing the MXI1 and ADRA2A genes. Genomics. 45 (2), pp. 407-411. https://doi.org/10.1006/geno.1997.4924

Taxonomic and biogeographic analysis of the Proasellus coxalis-group (Crustacea, Isopoda, Asellidae) in Sicily, with description of Proasellus montalentii n.sp.
Stoch, F., Valentino, F. and Volpi, E. 1996. Taxonomic and biogeographic analysis of the Proasellus coxalis-group (Crustacea, Isopoda, Asellidae) in Sicily, with description of Proasellus montalentii n.sp. Hydrobiologia. 317, pp. 247-258. https://doi.org/10.1007/bf00036474

More detailed characterization of some of the HL60 karyotypic features by fluorescence in situ hybridization.
Volpi, E.V., Vatcheva, R., Labella, T. and Gan, S.U. 1996. More detailed characterization of some of the HL60 karyotypic features by fluorescence in situ hybridization. Cancer Genetics and Cytogenetics. 87 (2), pp. 103-106. https://doi.org/10.1016/0165-4608(95)00214-6

Molecular and genetic studies on the region of translocation and duplication in the neuroblastoma cell line NGP at the 1p36.13-p36.32 chromosomal site
Casciano, I., Marchi, J.V.M., Muresu, R., Volpi, E.V., Rozzo, C., Opdenakker, G. and Romani, M. 1996. Molecular and genetic studies on the region of translocation and duplication in the neuroblastoma cell line NGP at the 1p36.13-p36.32 chromosomal site. Oncogene. 12 (10), pp. 2101-2108.

Simple DNA repeats and sex chromosome differentiation in asellus aquaticus (Crustacea, isopoda)
Volpi, E.V., Pelliccia, F., Lanza, V., Barzotti, R. and Rocchi, A. 1995. Simple DNA repeats and sex chromosome differentiation in asellus aquaticus (Crustacea, isopoda). Heredity. 75, p. 267–272. https://doi.org/10.1038/hdy.1995.134

Cytogenetic and molecular studies on the neuroblastoma cell line NGP: identification of a reciprocal t(1;15) involving the "consensus region" 1p36.1.
Muresu, R., Casciano I., Volpi, E.V., Siniscalco, M. and Romani, M. 1995. Cytogenetic and molecular studies on the neuroblastoma cell line NGP: identification of a reciprocal t(1;15) involving the "consensus region" 1p36.1. Genes, Chromosomes & Cancer. 13 (1), pp. 66-71. https://doi.org/10.1002/gcc.2870130111

Subregional mapping of the human lymphocyte-specific protein tyrosine kinase gene (LCK) to 1p35-->p34.3 and its position relative to the 1p marker D1S57.
Volpi, E.V., Romani, M. and Siniscalco, M. 1994. Subregional mapping of the human lymphocyte-specific protein tyrosine kinase gene (LCK) to 1p35-->p34.3 and its position relative to the 1p marker D1S57. Cytogenetics and Cell Genetics. 67, pp. 187-189. https://doi.org/10.1159/000133819

Telomeric sequences of ase/lus aquaticus (Crust. isop.)
Pelliccia, F., Volpi, E.V., Lanza, V., Gaddini, L., Balding, A. and Rocchi, A. 1994. Telomeric sequences of ase/lus aquaticus (Crust. isop.). Heredity. 72, pp. 78-80. https://doi.org/10.1038/hdy.1994.9

Concurrent mapping of an adenovirus 5/SV40 integration site and the U1 snRNA cluster (RNU1) within 400 kb of the chromosome region 1p36.1.
Romani, M., Baldini, A., Volpi, E., Casciano, I., Nobile, C., Muresu, R. and Siniscalco, M. 1994. Concurrent mapping of an adenovirus 5/SV40 integration site and the U1 snRNA cluster (RNU1) within 400 kb of the chromosome region 1p36.1. Cytogenetics and Cell Genetics. 67, pp. 37-40. https://doi.org/10.1159/000133793

MULTIPRINS: a method for multicolour primed in situ labelling
Volpi, E. and Baldini, A. 1993. MULTIPRINS: a method for multicolour primed in situ labelling. Chromosome Research. 1, pp. 257-260. https://doi.org/10.1007/bf00710131

Morphological differentiation of a sex chromosome and ribosomal genes in asellus aquaticus (Crust. Isop.)
Volpi, E.V., Pelliccia, F., Lanza, V., Di Castro, M. and Rocchi, A. 1992. Morphological differentiation of a sex chromosome and ribosomal genes in asellus aquaticus (Crust. Isop.). Heredity. https://doi.org/10.1038/hdy.1992.153

GATA repeats in the genome of Asellus aquaticus (Crustacea, Isopoda).
Pelliccia, F., Di Castro, M., Lanza, V., Volpi, E.V. and Rocchi, A. 1991. GATA repeats in the genome of Asellus aquaticus (Crustacea, Isopoda). Chromosoma. 100, pp. 152-155. https://doi.org/10.1007/bf00337243

Light-dark cycle and mitotic index in Asellus aquaticus (L.) (Crustacea, Isopoda)
Valentino, F., Volpi, E.V., Antolini, R. and Migliore, L. 1990. Light-dark cycle and mitotic index in Asellus aquaticus (L.) (Crustacea, Isopoda). Genetica. 82, pp. 147-150. https://doi.org/10.1007/bf00124645

The genetic isolation between some populations of Proasellus coxalis
Volpi, E.V., Antolini, R. and Valentino, F. 1989. The genetic isolation between some populations of Proasellus coxalis. Journal of Zoological Systematics and Evolutionary Research. 27 (3), pp. 246-251. https://doi.org/10.1111/j.1439-0469.1989.tb00346.x

Characterization of the karyotype of proasellus meridianusby differential staining techniques
Di Castro, M., Lanza, V., Volpi, E.V. and Rocchi, A. 1989. Characterization of the karyotype of proasellus meridianusby differential staining techniques. Caryologia. 42 (3-4), pp. 235-242. https://doi.org/10.1080/00087114.1989.10796970

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