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Detection of Neuritic Plaques in Alzheimer's Disease Mouse Model
Published on: July 26, 2011
Cerebral organoids with chromosome 21 trisomy secrete Alzheimer's disease-related soluble aggregates detectable by
Emre Fertan1,2, Dorothea Böken1,2, Aoife Murray3,4
1Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK.
Abstract:
Understanding the role of small, soluble aggregates of beta-amyloid (Aβ) and tau in Alzheimer's disease (AD) is of great importance for the rational design of preventative therapies. Here we report a set of methods for the detection, quantification, and characterisation of soluble aggregates in conditioned media of cerebral organoids derived from human iPSCs with trisomy 21, thus containing an extra copy of the amyloid precursor protein (APP) gene. We detected soluble beta-amyloid (Aβ) and tau aggregates secreted by cerebral organoids from both control and the isogenic trisomy 21 (T21) genotype. We developed a novel method to normalise measurements to the number of live neurons within organoid-conditioned media based on glucose consumption. Thus normalised, T21 organoids produced 2.5-fold more Aβ aggregates with a higher proportion of larger (300-2000 nm2) and more fibrillary-shaped aggregates than controls, along with 1.3-fold more soluble phosphorylated tau (pTau) aggregates, increased inflammasome ASC-specks, and a higher level of oxidative stress inducing thioredoxin-interacting protein (TXNIP). Importantly, all this was detectable prior to the appearance of histological amyloid plaques or intraneuronal tau-pathology in organoid slices, demonstrating the feasibility to model the initial pathogenic mechanisms for AD in-vitro using cells from live genetically pre-disposed donors before the onset of clinical disease. Then, using different iPSC clones generated from the same donor at different times in two independent experiments, we tested the reproducibility of findings in organoids. While there were differences in rates of disease progression between the experiments, the disease mechanisms were conserved. Overall, our results show that it is possible to non-invasively follow the development of pathology in organoid models of AD over time, by monitoring changes in the aggregates and proteins in the conditioned media, and open possibilities to study the time-course of the key pathogenic processes taking place.
Insights
Early Alzheimer's disease (AD) pathology, including beta-amyloid (Aβ) and tau aggregates, was detected in cerebral organoids before plaque formation. This breakthrough allows for early in-vitro modeling of AD mechanisms.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Soluble aggregates of beta-amyloid (Aβ) and tau are critical in Alzheimer's disease (AD) pathogenesis.
- Developing preventative therapies requires understanding early AD mechanisms.
- Cerebral organoids offer a model for studying human brain development and disease.
Purpose of the Study:
- To develop methods for detecting and quantifying soluble Aβ and tau aggregates in cerebral organoid-conditioned media.
- To characterize early pathogenic changes in organoids modeling trisomy 21 (T21) Down syndrome, a genetic risk factor for AD.
- To establish a reproducible in-vitro model for studying the initial stages of AD pathogenesis.
Main Methods:
- Generation of cerebral organoids from human induced pluripotent stem cells (iPSCs) with and without trisomy 21 (T21).
- Detection and quantification of soluble Aβ and tau aggregates in conditioned media.
- Development of a novel normalization method based on glucose consumption to account for live neuron numbers.
Main Results:
- T21 organoids produced significantly higher levels of soluble Aβ aggregates (2.5-fold) with larger and more fibrillary shapes compared to controls.
- T21 organoids showed increased soluble phosphorylated tau (pTau) aggregates (1.3-fold), elevated inflammasome ASC-specks, and higher oxidative stress (TXNIP).
- These pathological changes were detectable in conditioned media prior to histological evidence of amyloid plaques or intraneuronal tau pathology in organoid slices.
Conclusions:
- Cerebral organoids from T21 iPSCs can model early AD pathogenic mechanisms, including soluble aggregate formation, before overt neuropathology.
- Non-invasive monitoring of conditioned media allows for tracking AD pathology development over time in organoid models.
- This approach provides a valuable platform for studying AD pathogenesis and testing preventative therapies in a pre-clinical setting.
