CD56bright NK cells play a significant role in neurodegenerative diseases such as multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). These cells are potent cytokine producers and are considered more immunoregulatory and less terminally differentiated than their CD56dim counterparts, which are primarily cytotoxic. The distinct functions of these subsets complicate understanding their roles in neurodegeneration. CD56bright NK cells can migrate into the central nervous system (CNS) and may exert neuroprotective effects, such as inhibiting autoreactive T cells in MS. However, their role in other diseases like AD is less clear, with some studies suggesting a detrimental effect due to cytokine secretion. The mechanisms underlying their migration into the CNS involve chemokine receptors and adhesion molecules, which differ between subsets. CD56bright NK cells are more prevalent in secondary lymphoid tissues, while CD56dim NK cells dominate peripheral blood. In MS, CD56bright NK cells accumulate in periventricular areas and may interact with other immune cells, modulating local immune responses. Their ability to suppress autoreactive T cells through granzyme K and PD-L1 expression suggests a potential protective role, although their function may be impaired in MS due to increased HLA-E expression. In EAE models, NK cells show conflicting roles, with some studies indicating protective effects and others suggesting pathogenic roles. Therapies like daclizumab, which target IL-2Rα, may enhance CD56bright NK cell activity, but have been withdrawn due to adverse effects. Overall, the role of CD56bright NK cells in neurodegenerative diseases remains complex, with potential therapeutic implications for future interventions.CD56bright NK cells play a significant role in neurodegenerative diseases such as multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). These cells are potent cytokine producers and are considered more immunoregulatory and less terminally differentiated than their CD56dim counterparts, which are primarily cytotoxic. The distinct functions of these subsets complicate understanding their roles in neurodegeneration. CD56bright NK cells can migrate into the central nervous system (CNS) and may exert neuroprotective effects, such as inhibiting autoreactive T cells in MS. However, their role in other diseases like AD is less clear, with some studies suggesting a detrimental effect due to cytokine secretion. The mechanisms underlying their migration into the CNS involve chemokine receptors and adhesion molecules, which differ between subsets. CD56bright NK cells are more prevalent in secondary lymphoid tissues, while CD56dim NK cells dominate peripheral blood. In MS, CD56bright NK cells accumulate in periventricular areas and may interact with other immune cells, modulating local immune responses. Their ability to suppress autoreactive T cells through granzyme K and PD-L1 expression suggests a potential protective role, although their function may be impaired in MS due to increased HLA-E expression. In EAE models, NK cells show conflicting roles, with some studies indicating protective effects and others suggesting pathogenic roles. Therapies like daclizumab, which target IL-2Rα, may enhance CD56bright NK cell activity, but have been withdrawn due to adverse effects. Overall, the role of CD56bright NK cells in neurodegenerative diseases remains complex, with potential therapeutic implications for future interventions.