obig3mu1

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?: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.
is ?:annotates of	<https://research.tib.eu/covid-19/entity/obig3mu1_hasAnnotation_C0017372> <https://research.tib.eu/covid-19/entity/obig3mu1_hasAnnotation_C0020517> <https://research.tib.eu/covid-19/entity/obig3mu1_hasAnnotation_C1412728>
?:creator	<https://research.tib.eu/covid-19/entity/Ali%C4%87%2C_Ivan%3B_Goh%2C_Pollyanna_A%3B_Murray%2C_Aoife%3B_Portelius%2C_Erik%3B_Gkanatsiou%2C_Eleni%3B_Gough%2C_Gillian%3B_Mok%2C_Kin_Y%3B_Koschut%2C_David%3B_Brunmeir%2C_Reinhard%3B_Yeap%2C_Yee_Jie%3B_O%E2%80%99Brien%2C_Niamh_L%3B_Groet%2C_Jurgen%3B_Shao%2C_Xiaowei%3B_Havlicek%2C_Steven%3B_Dunn%2C_N_Ray%3B_Kvartsberg%2C_Hlin%3B_Brinkmalm%2C_Gunnar%3B_Hithersay%2C_Rosalyn%3B_Startin%2C_Carla%3B_Hamburg%2C_Sarah%3B_Phillips%2C_Margaret%3B_Pervushin%2C_Konstantin%3B_Turmaine%2C_Mark%3B_Wallon%2C_David%3B_Rovelet-Lecrux%2C_Anne%3B_Soininen%2C_Hilkka%3B_Volpi%2C_Emanuela%3B_Martin%2C_Joanne_E%3B_Foo%2C_Jia_Nee%3B_Becker%2C_David_L%3B_Rostagno%2C_Agueda%3B_Ghiso%2C_Jorge%3B_Krsnik%2C_%C5%BDeljka%3B_%C5%A0imi%C4%87%2C_Goran%3B_Kostovi%C4%87%2C_Ivica%3B_Mitre%C4%8Di%C4%87%2C_Dinko%3B_Francis%2C_Paul_T%3B_Blennow%2C_Kaj%3B_Strydom%2C_Andre%3B_Hardy%2C_John%3B_Zetterberg%2C_Henrik%3B_Ni%C5%BEeti%C4%87%2C_Dean>
?:doi	10.1101/2020.01.29.918037
?:doi	<https://research.tib.eu/covid-19/entity/10.1101/2020.01.29.918037>
?:externalLink	<https://doi.org/10.1101/2020.01.29.918037>
?:journal	bioRxiv
?:license	biorxiv
?:pdf_json_files	document_parses/pdf_json/1d17b2f5c76d2380a864d23d772d160fbdcfd8ee.json
?:publication_isRelatedTo_Disease	<https://research.tib.eu/covid-19/entity/COVID-19>
?:sha_id	<https://research.tib.eu/covid-19/entity/1d17b2f5c76d2380a864d23d772d160fbdcfd8ee>
?:source	BioRxiv
?:title	“Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene-dose-sensitive AD-suppressor in human brain”
?:type	<https://research.tib.eu/covid-19/vocab/Publication>
?:year	2020-01-31

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?: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.

is ?:annotates of