Neural stem cells (NSCs) – the reservoir for new neurons – can be harnessed for stem cell-based regenerative therapies in the human brain. In Alzheimer’s disease (AD), production of new neurons is suppressed due to hampered proliferative and neurogenic ability of NSCs. Therefore, understanding how the plasticity of NSCs could be induced would be important for designing stem cell‑based therapies for AD. Zebrafish have a remarkable ability to regenerate the brain as they can induce NSC plasticity. However, it is still unknown whether the NSC population in the zebrafish brain is heterogeneous and different subtypes could respond differently to disease pathology. We recently identified that NSCs enhance their proliferation and neurogenic outcomes in an Amyloid‑beta42‑based (Aβ42) experimental AD model in the zebrafish brain and Interleukin‑4 (IL4) is a critical molecule for inducing NSC proliferation in AD conditions and this regulation is also observed in human NSCs. However, the mechanisms by which Aβ42 and IL4 affect NSCs remains unknown. Using single cell transcriptomics, we determined distinct subtypes of NSCs and neurons in adult zebrafish telencephalon and identified a novel and IL4‑dependent crosstalk mechanism that controls NSC plasticity in AD conditions in adult fish brain and human 3D cultures. Our results constitute an extensive set of resource in the AD model of adult zebrafish brain and provide unique insights into how Aβ42 and IL4 affect NSC plasticity and neurogenesis.
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