Neurons derived from individual early Alzheimer's disease patients reflect their clinical vulnerability

Abstract

Establishing preclinical models of Alzheimer's disease that predict clinical outcomes remains a critically important, yet to date not fully realized, goal. Models derived from human cells offer considerable advantages over non-human models, including the potential to reflect some of the inter-individual differences that are apparent in patients. Here we report an approach using induced pluripotent stem cell-derived cortical neurons from people with early symptomatic Alzheimer's disease where we sought a match between individual disease characteristics in the cells with analogous characteristics in the people from whom they were derived. We show that the response to amyloid-β burden in life, as measured by cognitive decline and brain activity levels, varies between individuals and this vulnerability rating correlates with the individual cellular vulnerability to extrinsic amyloid-β in vitro as measured by synapse loss and function. Our findings indicate that patient-induced pluripotent stem cell-derived cortical neurons not only present key aspects of Alzheimer's disease pathology but also reflect key aspects of the clinical phenotypes of the same patients. Cellular models that reflect an individual's in-life clinical vulnerability thus represent a tractable method of Alzheimer's disease modelling using clinical data in combination with cellular phenotypes.

Keywords: Alzheimer’s disease; clinical vulnerability; disease modelling; induced pluripotent stem cells; synapse loss.

Graphical Abstract

Figure 1

Levels of secreted Aβ from Alzheimer’s disease patient iPSC-derived cortical neurons correlated with patient CSF Aβ levels. Pairwise comparisons between the levels of secreted Aβ species from the patient-derived neurons and the levels of the same Aβ species in the patient’s CSF. Error band: 95% confidence interval (CI). There were n = 36 independent neuronal differentiation repeats per patient line. Pearson’s coefficient of correlation and its P-value were reported for statistical analysis.

Figure 2

Extrinsic Aβ insults resulted in a spectrum of vulnerability resulting in synapse loss in patient iPSC-derived cortical neurons. Representative immunofluorescence images from three selected patient lines ranging from the least to the most vulnerable to Aβ_1-42 oligomer insults relative to the scrambled peptide control treatment. The images are labelled with presynaptic (Synapsin I/II), post-synaptic (Homer1) and dendritic (MAP2) markers. White arrows indicate synapse examples with pre- and post-synaptic markers in apposition. Scale bar = 50 μm.

Figure 3

Synaptic vulnerability to extrinsic Aβ insults in patient iPSC-derived cortical neurons remained consistent across neuronal differentiation repeats and types of Aβ insults. Pairwise comparisons of the degrees of synapse loss between neuronal differentiation repeats caused by Aβ_1-42, Aβ_25-35 oligomers or Alzheimer’s disease brain homogenate. The same three selected patient lines from Fig. 2 are highlighted in the graphs. Pearson’s coefficient of correlation and its P-value were reported for statistical analysis.

Figure 4

Synapse loss due to Aβ insults in vitro reflects clinical vulnerability in the same patients to Aβ burden in vivo. Pairwise comparisons between the percentage of synapse loss and clinical vulnerability quotients. Each row denotes the type of extrinsic Aβ insult used to induce synapse loss and each column denotes the selected clinical outcomes which have been corrected for Aβ_1-42 concentration in the CSF (MMSE score loss rate) or amyloid PET SUVR (MEG). Error band: 95% confidence interval (CI). n = 35 (Aβ_1-42—MMSE score loss rate), 36 (Aβ_25-35 and Alzheimer’s disease brain homogenate—MMSE score loss rate) and 24 (all MEG) independent neuronal differentiation repeats per patient line. Pearson’s coefficient of correlation and its P-value were reported for statistical analysis.

Figure 5

Reductions in neuronal activity due to Aβ_1-42 insults in vitro reflect synaptic vulnerability in the same patient lines. Comparison of the resilient group (Patients #9, #6 and #5) and vulnerable group (Patients #7, #13 and #11) neuronal responses in their FR and BR to Aβ_1-42 10 μM on the second day of incubation. The vulnerable group showed a greater decrease in activity compared to the resilient group in both FR and BR. Each datapoint represents an electrode recording. n = 22 (#9), 114 (#6), 7 (#5), 49 (#7), 24 (#13) and 41 (#11) for the FR data, whereas n = 17 (#9), 93 (#6), 2 (#5), 43 (#7), 18 (#13) and 29 (#11) for the BR data. The percentage change from baseline was normalized against changes in untreated media control. Mean ± SEM; two-tailed Welch’s t-test was used for statistical analysis comparing the combined data of the resilient and vulnerable groups. P = 0.018 and t = 3.90 for the FR data and P = 0.016 and t = 4.11 for the BR data.