Late onset or sporadic Alzheimer's disease accounts for over 95% of cases and is therefore the most prevalent form of the syndrome that leads to progressive neuronal atrophy and memory impairment. While sporadic disease is diagnosed on average at ~60 years of age, the first pathological changes commonly go unnoticed and may occur over 10 years before cognitive impairment is evident.
One major challenge faced by the Alzheimer's research community is the lack of mouse models replicating sporadic Alzheimer's disease pathology to enable elucidating disease mechanisms and testing potential therapeutics. The majority of Alzheimer's mouse models developed to date, and the most commonly used, are successful at replicating pathological hallmarks of the familial or early onset disease, which is a far less frequent (5%) condition (Foidl and Humpel 2020).
Partly, the challenge in developing a mouse model of sporadic Alzheimer's disease relates to its complex origin. Currently, it's clear that several factors contribute to the development of sporadic disease. For example, specific genetic (e.g., APOE e4 and TREM2 variants), age-associated lifestyle related (e.g., hypertension, hypercholesterolemia, and diabetes) and environmental factors have been proposed to increase the risk of Alzheimer's disease (Rabinovici 2019, Scearce-Levie et al. 2020). Ultimately, mouse models are unable to help elucidate the role of aging as a critical risk factor in sporadic Alzheimer's disease.
Cerebral organoids produced from patient derived induced pluripotent stem cells (iPSCs) have shed light on the molecular bases of several neurodevelopmental disorders, such as microcephaly and Timothy syndrome, each underscored by mutations in the CDK5RAP2 and CACNA1C genes, respectively (Eremeev et al. 2021). Similarly, cerebral organoids have already shown to be valuable tools in understanding disease mechanisms in various neurodegenerative conditions, such as Huntington's and Parkinson's disease (Conforti et al. 2018, Kim et al. 2019).
Basic strategies to produce cerebral organoids from PSCs. The preparatory stage includes various approaches for obtaining spheroids with or without preliminary differentiation into neuroepithelial progenitors. Then, the spheroids form cerebral organoids during long-term cultivation under stationary or dynamic culture conditions. DMP-dorsomorphin; SB- SB431542; LDN-LDN193189. Retrieved without modifications from Figure 1 (Eremeev et al. 2021) ( https://creativecommons.org/licenses/by/4.0/
For Alzheimer's disease modeling, Gonzalez and colleagues had shown the feasibility of utilizing patient derived iPSCs for generating cerebral organoids that replicate pathological features of the disease, such as the formation of amyloid beta and tau aggregates, verifiable through immunostaining. Therefore, human derived cerebral organoids with their 3D and cortical-like organization provide a useful setting to expand our understanding of Alzheimer's pathology and to identify new therapeutic strategies.
Understanding the dire need for effective disease modeling in Alzheimer's research, JC Park and colleagues at the College of Medicine, Seoul National University, recently developed a cerebral organoid based platform for high content screening of drugs to help identify therapies for Alzheimer's disease (Park et al. 2021). They focused on the predominant form of the disease by deriving iPSCs from sporadic Alzheimer patient's cells. Over a thousand organoids were generated from a total of 11 patients and leveraged to evaluate the efficacy of FDA approved drugs. Drug validation was based on two main assays, which measured cell death and levels of amyloid beta and tau aggregates.
Park and colleagues first confirmed the validity of their in vitro model by verifying the presence of several Alzheimer's pathological features. For instance, they found that cerebral organoids derived from Alzheimer's patients having positron emission tomography (PET+) confirmed amyloid beta plaques, had greater extracellular amyloid beta and intracellular phosphorylated tau aggregates, compared to cerebral organoids from PET negative patients. Additionally, PET+ cerebral organoids had higher calcium activity indicative of abnormal calcium regulation, and reduced expression of genes involved in synaptic function and neurogenesis.
Having verified the validity of their model system, and informed by mathematical modeling highlighting relevant signaling pathways, Park and colleagues screened a number of FDA approved drugs in PET+ cerebral organoids. Some of the selected drugs targeted ApoE e4 relevant pathways. They found that several drug combinations (e.g., Flibanserin and Ripasudil) were variably effective at reducing pathogenic protein deposition and improving cell viability. Overall, through this work investigators demonstrated the power of a high quality cerebral organoid platform as a model system in Alzheimer's research with the potential to facilitate and expedite the discovery of therapeutic strategies to tackle Alzheimer's complex pathologies.