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Alzheimer‐like pathology in trisomy 21 cerebral organoids amenable to pharmacological inhibition reveals BACE2 as a gene‐dose‐sensitive AD‐suppressor in human brain
Author(s) -
Alic Ivan,
Goh Pollyanna,
Murray Aoife,
Portelius Erik,
Gough Gillian,
Gkanatsiou Eleni,
Wallon David,
RoveletLecrux Anne,
Rostagno Agueda,
Ghiso Jorge,
Francis Paul T.,
Strydom Andre,
Hardy John,
Zetterberg Henrik,
Nizetic Dean
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.043136
Subject(s) - organoid , induced pluripotent stem cell , amyloid precursor protein , biology , neprilysin , trisomy , microbiology and biotechnology , cancer research , alzheimer's disease , medicine , embryonic stem cell , genetics , gene , disease , biochemistry , enzyme
Abstract Background 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 (APP). This is in contrast to non‐DS patients who inherit just the duplication of the APP gene (DupAPP), who develop EOAD with 100% penetrance, raising hypotheses of potential other AD‐suppressing genes on chromosome 21. Method Cerebral organoids were grown in vitro from isogenic T21 and normal induced‐pluripotent‐stem‐cells (iPSCs), as well as a DupAPP patient. Trisomy of chromosome‐21 gene BACE2 was corrected to disomy by CRISPR/Cas9 editing. Organoids were analysed histologically and organoid pools profiled for β‐amyloid secretion by immunoprecipitation‐mass spectrometry (IP‐MS). Tissue‐quantity‐independent peptide ratios were compared between organoid conditioned media (CM) and cerebrospinal fluid (CSF) from DS and age‐matched euploid individuals. Result We found that T21, but not DupAPP, organoids secrete increased proportions of putative BACE2‐θ‐secretase (Aβ1‐19) and BACE2‐Aβ‐degrading protease (AβDP or Aβ‐clearance) products (Aβ1‐20 and Aβ1‐34) compared to isogenic normal controls. Increased ratios of BACE2‐related to BACE2‐unrelated anti‐amyloidogenic cleavages were reproduced in CSF of people with DS, mirroring organoid secretions. Finally, CRISPR/SpCas9‐HF1‐reduction of BACE2 (3 to 2 copies) in T21‐iPSC significantly decreased AβDP/amyloidogenic ratio and triggered early and accelerated AD‐like pathology in T21 organoids. The pathology consisted of insoluble amyloid plaque‐like deposits, fibrillar aggregates, pathologically altered Tau, and premature neuronal loss, and was preventable by an early application of a combination of β‐secretase and γ‐secretase inhibitors. Conclusion Our combined data demonstrate the role of BACE2 as a genetic‐dose‐dependent AD‐suppressor in human brain, and organoid technology as a potential assay for screening for other protective genes and disease‐preventive drugs.