The lncRNA Neat1 is associated with astrocyte reactivity and memory deficits in a mouse model of Alzheimer’s disease

Dysregulation of long non-coding RNAs (lncRNAs) have been associated with Alzheimer’s disease (AD). However, the functional role of lncRNAs in AD remains unclear. Here, we report a crucial role for the lncRNA Neat1 in astrocyte dysfunction and memory deficits associated with AD. Transcriptomics analysis show abnormally high expression levels of NEAT1 in the brains of AD patients relative to aged-matched healthy controls, with the most significantly elevated levels in glial cells. In a human transgenic APP-J20 (J20) mouse model of AD, RNA-fluorescent in situ hybridization characterization of Neat1 expression in hippocampal astrocyte versus non-astrocyte cell populations revealed a significant increase in Neat1 expression in astrocytes of male, but not female, mice. This corresponded with increased seizure susceptibility in J20 male mice. Interestingly, Neat1 deficiency in the dCA1 in J20 male mice did not alter seizure threshold. Mechanistically, Neat1 deficiency in the dorsal area CA1 of the hippocampus (dCA1) J20 male mice significantly improved hippocampus-dependent memory. Neat1 deficiency also remarkably reduced astrocyte reactivity markers suggesting that Neat1 overexpression is associated with astrocyte dysfunction induced by hAPP/Aβ in the J20 mice. Together, these findings indicate that abnormal Neat1 overexpression may contribute to memory deficits in the J20 AD model not through altered neuronal activity, but through astrocyte dysfunction.