Deciphering the microenvironment of adult neurogenesis: a perspective from neurodegenerative diseases

Abstract Neurodegenerative diseases are characterized by progressive neuron loss and brain atrophy. While conventional studies focused on neuronal death as the primary cause of these diseases, accumulating evidence suggests that impaired neurogenesis, particularly the dysfunction of adult neural stem cells (NSCs), may also contribute significantly to disease pathogenesis. Adult neurogenesis occurs primarily in two adult NSC niches. These specialized niches are enriched with complex cytokine networks, neuronal activity, and non-cellular components such as the extracellular matrix. Understanding the regulation of NSCs in the adult brain and how their dysregulation exacerbates neurodegeneration provides novel insights into therapeutic strategies. This review proposes that dysfunction of the NSC microenvironment, rather than neuronal death alone, may drive neurodegeneration, and that restoring this microenvironment offers a novel research direction of stem cell-based therapies.