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/Aß 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.

A putative role for lncRNAs in epigenetic regulation of memory.

The central dogma of molecular genetics is defined as encoded genetic information within DNA, transcribed into messenger RNA, which contain the instructions for protein synthesis, thus imparting cellular functionality and ultimately life. This molecular genetic theory has given birth to the field of neuroepigenetics, and it is now well established that epigenetic regulation of gene transcription is critical to the learning and memory process. In this review, we address a potential role for a relatively new player in the field of epigenetic crosstalk - long non-coding RNAs (lncRNAs). First, we briefly summarize epigenetic mechanisms in memory formation and examine what little is known about the emerging role of lncRNAs during this process. We then focus discussions on how lncRNAs interact with epigenetic mechanisms to control transcriptional programs under various conditions in the brain, and how this may be applied to regulation of gene expression necessary for memory formation. Next, we explore how epigenetic crosstalk in turn serves to regulate expression of various individual lncRNAs themselves. To highlight the importance of further exploring the role of lncRNA in epigenetic regulation of gene expression, we consider the significant relationship between lncRNA dysregulation and declining memory reserve with aging, Alzheimer's disease, and epilepsy, as well as the promise of novel therapeutic interventions. Finally, we conclude with a discussion of the critical questions that remain to be answered regarding a role for lncRNA in memory.

The SETD6 Methyltransferase Plays an Essential Role in Hippocampus-Dependent Memory Formation.

BACKGROUND: Epigenetic mechanisms are critical for hippocampus-dependent memory formation. Building on previous studies that implicate the N-lysine methyltransferase SETD6 in the activation of nuclear factor-κB RELA (also known as transcription factor p65) as an epigenetic recruiter, we hypothesized that SETD6 is a key player in the epigenetic control of long-term memory. METHODS: Using a series of molecular, biochemical, imaging, electrophysiological, and behavioral experiments, we interrogated the effects of short interfering RNA-mediated knockdown of Setd6 in the rat dorsal hippocampus during memory consolidation. RESULTS: Our findings demonstrate that SETD6 is necessary for memory-related nuclear factor-κB RELA methylation at lysine 310 and associated increases in H3K9me2 (histone H3 lysine 9 dimethylation) in the dorsal hippocampus and that SETD6 knockdown interferes with memory consolidation, alters gene expression patterns, and disrupts spine morphology. CONCLUSIONS: Together, these findings suggest that SETD6 plays a critical role in memory formation and may act as an upstream initiator of H3K9me2 changes in the hippocampus during memory consolidation.