Neuronal CD59 isoforms IRIS-1 and IRIS-2 as regulators of neurotransmitter release with implications for Alzheimer's disease.

We have previously demonstrated that the intracellular, non-GPI anchored CD59 isoforms IRIS-1 and IRIS-2 (Isoforms Rescuing Insulin Secretion 1 and 2) are necessary for insulin secretion from pancreatic β-cells. While investigating their expression across human tissues, we identified IRIS-1 and IRIS-2 mRNA in the human brain, though their protein expression and function remained unclear. This study shows the presence of both IRIS-1 and 2 proteins in the human brain, specifically in neurons and astrocytes. In the neuroblastoma cell line (SH-SY5Y), both isoforms are intracellular, and their expression increases upon differentiation into mature neurons. Silencing IRIS-1 and 2 in SH-SY5Y cells reduces the SNARE complex formation, essential for synaptic vesicle exocytosis, leading to a reduction in noradrenaline secretion. Notably, we observed diminished expression of neuronal IRIS-1 and 2 in patients with Alzheimer's disease (AD) and non-demented individuals with type 2 diabetes (T2D). In SH-SY5Y cells, knockdown of all isoforms of CD59 including IRIS-1 and 2 not only elevates phosphorylated tau but also increases cyclin-dependent kinase 5 (CDK5) expression, known promoter of hyperphosphorylation and accumulation of tau, a key pathological feature of AD. Additionally, we found that prolonged exposure to high glucose or cytokines markedly reduces the expression of IRIS-1 and 2 in SH-SY5Y cells, suggesting a link between AD pathology and metabolic stress through modulation of these isoforms. Significance statement: The study reveals the existence of intracellular, non-GPI anchored CD59 isoforms IRIS-1 and IRIS-2 in neurons and astrocytes within the human brain. It also demonstrates decreased expression of IRIS-1 and 2 in neurons of individuals with AD and T2D, pointing to a link between aberrant expression of IRIS isoforms and deficiencies in neurotransmitter release in patients with AD. Identifying specific IRIS-1 and IRIS-2 binding partners within the neurons and the exact mechanism leading to its reduced expression in AD could provide new therapeutic targets to delay the symptomatic progression of Alzheimer's disease. [ABSTRACT FROM AUTHOR]