The Impact of APP on Alzheimer-like Pathogenesis and Gene Expression in Down Syndrome iPSC-Derived Neurons

Ovchinnikov, Dmitry A.; Korn, Othmar; Virshup, Isaac; Wells, Christine A.; Wolvetang, Ernst J.

doi:10.1016/j.stemcr.2018.05.004

Cited by 57 publications

(49 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…protection. An integration of the two observations (the one in 47 and the one in our report) suggests this could be exploited as an additional new protective/therapeutic strategy for AD in general.…”

Section: All Of the Above Data (And New Data We Show Insupporting

confidence: 63%

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

Alić

Goh

Murray

et al. 2020

Preprint

View full text Add to dashboard Cite

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 T21organoids 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 crossinhibited 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.These studies uncovered that BACE2 can cleave the product of β-secretase (APP β-CTF) between aa19 and aa20, generating a 1-19 fragment [13][14][15] , thereby potentially preventing the formation of amyloidogenic Aβ, and degrading the β-CTF that has been implicated in neuronal toxicity, and impairment of several neuronal functions, such as axonal transport and autophagy 16 .When offered synthetic Aβ40/42 peptides in solution, purified BACE2 protein can rapidly degrade them by cutting after aa20 and aa34, to generate the 1-20 and 1-34 peptide products, but only at very acidic pH (3.5-4). In this reaction, BACE2 is 150-fold more efficient than BACE1, which is also capable of this cleavage, upon conditions of increased enzyme concentration/time 12,14 . Neither of these two putative anti-amyloidogenic actions of BACE2 (the θ-secretase activity, generating aa1-19, or the Aβ-degrading-protease activity (AβDP or Aβ clearance) generating aa1-20 and aa1-34), have yet been demonstrated to be the functional role of BACE2 under physiologically fluctuating gene doses in vivo in the human brain. A naturally occurring form of gene overdose for both APP and BACE2 is DS, caused by the trisomy of human chromosome 21 (T21) that harbours both APP and BACE2 genes. As increased levels of soluble Aβ were observed already in foetal brains in DS 17 , we examined cerebral organoids grown from induced pluripotent stem cell (iPSC) generated by non-integr...

show abstract

Section: All Of the Above Data (And New Data We Show Insupporting

confidence: 63%

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

Alić

Goh

Murray

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…DS patients develop early onset AD, thought to result from triplication of the APP gene as part of trisomy 21 [97]. DS iPSC-derived neurons show elevations in Aβ secretion and phosphorylated tau similar to that caused by FAD-linked mutations [98][99][100][101]. Intriguingly, deletion of the supernumerary copy of APP from DS cells was able to restore Aβ production to control levels and correct many of the gene expression alterations caused by trisomy 21, but was not able to restore altered tau phosphorylation, indicating Aβ-dependent and independent phenotypes in DS [101].…”

Section: Human Neural Progenitor Cell and Neuron Modelsmentioning

confidence: 99%

Modeling Alzheimer’s disease with iPSC-derived brain cells

2019

View full text Add to dashboard Cite

Alzheimer's disease is a devastating neurodegenerative disorder with no cure. Countless promising therapeutics have shown efficacy in rodent Alzheimer's disease models yet failed to benefit human patients. While hope remains that earlier intervention with existing therapeutics will improve outcomes, it is becoming increasingly clear that new approaches to understand and combat the pathophysiology of Alzheimer's disease are needed. Human induced pluripotent stem cell (iPSC) technologies have changed the face of preclinical research and iPSC-derived cell types are being utilized to study an array of human conditions, including neurodegenerative disease. All major brain cell types can now be differentiated from iPSCs, while increasingly complex co-culture systems are being developed to facilitate neuroscience research. Many cellular functions perturbed in Alzheimer's disease can be recapitulated using iPSC-derived cells in vitro, and co-culture platforms are beginning to yield insights into the complex interactions that occur between brain cell types during neurodegeneration. Further, iPSC-based systems and genome editing tools will be critical in understanding the roles of the numerous new genes and mutations found to modify Alzheimer's disease risk in the past decade. While still in their relative infancy, these developing iPSC-based technologies hold considerable promise to push forward efforts to combat Alzheimer's disease and other neurodegenerative disorders.

show abstract

“…Similarly, it may be the case that overexpression of APP due to trisomy 21 may precipitate downstream proteopathy (Aβ plaques, neurofibrillary tangles), synapse loss, cell death, and eventual cognitive decline (Glenner & Wong, 1984;Teller et al, 1996). However, recent perspectives have challenged whether an increased genetic dosage of APP is sufficient to explain the highly increased AD susceptibility seen in individuals with DS (Ovchinnikov, Korn, Virshup, Wells, & Wolvetang, 2018;Wiseman et al, 2018). The core histopathological features of AD are common to late onset Alzheimer's disease (LOAD), FAD, and DS-AD (Braak & Braak, 1994;Teller et al, 1996).…”

mentioning

confidence: 99%

Plasma metabolites related to cellular energy metabolism are altered in adults with Down syndrome and Alzheimer's disease

Groß

Doran

Cheema

et al. 2019

Developmental Neurobiology

View full text Add to dashboard Cite

Down syndrome (DS) is a well‐known neurodevelopmental disorder most commonly caused by trisomy of chromosome 21. Because individuals with DS almost universally develop heavy amyloid burden and Alzheimer's disease (AD), biomarker discovery in this population may be extremely fruitful. Moreover, any AD biomarker in DS that does not directly involve amyloid pathology may be of high value for understanding broader mechanisms of AD generalizable to the neurotypical population. In this retrospective biomarker discovery study, we examined banked peripheral plasma samples from 78 individuals with DS who met clinical criteria for AD at the time of the blood draw (DS‐AD) and 68 individuals with DS who did not (DS‐NAD). We measured the relative abundance of approximately 5,000 putative features in the plasma using untargeted mass spectrometry (MS). We found significantly higher levels of a peak putatively annotated as lactic acid in the DS‐AD group (q = .014), a finding confirmed using targeted MS (q = .011). Because lactate is the terminal product of glycolysis and subsequent lactic acid fermentation, we performed additional targeted MS focusing on central carbon metabolism which revealed significantly increased levels of pyruvic (q = .03) and methyladipic (q = .03) acids in addition to significantly lower levels of uridine (q = .007) in the DS‐AD group. These data suggest that AD in DS is accompanied by a shift from aerobic respiration toward the less efficient fermentative metabolism and that bioenergetically derived metabolites observable in peripheral blood may be useful for detecting this shift.

show abstract

The Impact of APP on Alzheimer-like Pathogenesis and Gene Expression in Down Syndrome iPSC-Derived Neurons

Cited by 57 publications

References 41 publications

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

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

Modeling Alzheimer’s disease with iPSC-derived brain cells

Plasma metabolites related to cellular energy metabolism are altered in adults with Down syndrome and Alzheimer's disease

Contact Info

Product

Resources

About