iPSC-derived neurospheres: A cellular platform for Tau and Alzheimer's disease immunotherapy

Alzheimer's disease is the most prevalent type of dementia, which is characterized by a progressive loss of memory and cognitive impairment. The internalization of extracellular Tau and Amyloid-β-induced pluripotent stem cells plays a crucial role in understanding the AD pathology. iPSC-derived neuron, microglia, and astrocyte are used as models to study the spreading of pathological proteins and their contribution in the disease progression. iPSC-derived neurons serve as an essential model for studying AD, particularly in relation to Tau aggregation, prion-like propagation, and the toxic effects of oligomeric amyloid beta. Extracellular Tau, along with oligomeric amyloid beta, enters neurons via endocytosis and macropinocytosis, leading to cellular abnormalities, oxidative stress, and dysfunction in neurons. Additionally, iPSC-derived microglia provide insights into neuroinflammatory responses and neurotoxic effects of Tau aggregation and Amyloid-β, highlighting their combined role in Alzheimer's pathology. Extracellular Tau internalization by microglia involves phagocytosis and exhibits activation response to Tau aggregates, releasing cytokines and undergoing calcium homeostasis. iPSC-derived astrocytes demonstrated a reactive state and disruption in calcium homeostasis upon the exposure of the pathological proteins, contributing to neurodegeneration. Further, the mechanisms of Tau and Amyloid-β internalization in iPSC-derived cells provide insights into disease progression and highlights potential therapeutic targets for neurodegenerative disease.