UNCOVERING MECHANISMS OF ALZHEIMER’S DISEASE DEVELOPMENT THROUGH IPSC- DERIVED CEREBRAL ORGANOIDS
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| Year of publication | 2024 |
| Type | Conference abstract |
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| Description | Alzheimer’s disease (AD) is a neurodegenerative disorder primarily characterized by the presence of amyloid plaques, neurofibrillary tangles, and loss of neuronal connections in the brain1. Nowadays, AD holds its position as the most prevalent cause of dementia in middle-aged and elderly individuals, and with the gradual extension of human life, it has become a significant health problem worldwide. Despite extensive efforts to explore various therapeutic approaches, AD remains an incurable disease. Consequently, scientists have turned their attention to enhancing in vitro models that more accurately replicate the pathophysiology observed in AD patients, aiming to achieve a deeper understanding of the disease’s biology. Currently, induced pluripotent stem cells (iPSCs) are widely utilized for investigating human neurodevelopment and diseases. In the context of AD, iPSCs have been used to generate three-dimensional cerebral organoids (COs), effectively mimicking AD pathology in vitro2. These in vitro models not only replicate AD pathology but also stimulate the early stages of brain development. As a result, they could play a crucial role in revealing the initiation steps and molecular mechanisms underlying this disease. These, however, remain to be described. In our laboratory, we recently generated iPSC lines from patients with the familial form of AD. Our AD cell lines carry mutations in PSEN1(A246E) and PSEN2(N141I) genes and are sex- and age-matched to non-demented controls (NDC)3. These cell lines were subsequently used to generate COs. Our previous data revealed that 60-days-old organoids not only manifested AD-like pathology but also had altered development4. Moreover, single-cell sequencing analysis suggested their premature differentiation. To explore the initial stages of Alzheimer's disease, we now examined the expression of genes associated with brain development and the activity of pathways crucial for neurodevelopment. Our findings thus far show that AD-COs undergo distinct developmental patterns. Specifically, AD-COs show a preference for the differentiation into prosencephalon, problems in proper dorsal-ventral development, and likely altered key signaling pathways, including Notch and Wnt. Further examination of these differences in the early stages of development will be the key pillar for understanding the initiation mechanisms of disease. |
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