MODELING ALZHEIMER'S DISEASE USING ORGANOIDS DERIVED FROM ADULT NEURAL STEM CELLS

Alzheimer’s disease (AD), the most prevalent form of dementia, is characterized by the accumulation of pathological proteins (including β-amyloid and Tau), neuronal and synaptic loss, chronic neuroinflammation, and blood-brain barrier disruption. While genetic, epigenetic and environmental factors contribute to the disease susceptibility, ageing remains the main risk factor.
To better understand the disease, several cellular models have been developed. Among these, cerebral organoids derived from embryonic or induced pluripotent stem cells (iPSCs) have emerged as advanced 3D models that partially recapitulate the tissue cytoarchitecture and microenvironment complexity. However, despite exhibiting the disease hallmarks, organoids from Alzheimer’s patient iPSCs present a major limitation for studying age-related diseases, as the reprogramming induces a profound epigenetic reset, erasing age-related molecular signatures.
In this context, mammalian adult neural stem cells (aNSCs) derived organoids provide a promising alternative. aNSCs in the subventricular zone (SVZ) retain the proliferation and differentiation capacities throughout life while preserving ageing signatures.
Here, we aim to develop aNSC-derived organoids that preserve cellular ageing signatures and recapitulate pathological features associated with AD.
We established aNSC–derived organoids from an Alzheimer’s disease mouse model and age-matched controls. AD-derived organoids showed altered growth dynamics, forming fewer and smaller structures compared with controls. Moreover, they exhibited accumulation of amyloid-β and phosphorylated tau, together with elevated expression of markers associated with neuroinflammation, as assessed by immunostaining. Collectively, these findings indicate that aNSC-derived organoids retain intrinsic Alzheimer's-related pathology features and provide a relevant platform for modeling age-related degeneration.