NACC2, a molecular effector of miR-132 regulation at the interface between adult neurogenesis and Alzheimer's disease

TY - JOUR

T1 - NACC2, a molecular effector of miR-132 regulation at the interface between adult neurogenesis and Alzheimer's disease

AU - Penning, Amber

AU - Snoeck, Sarah

AU - Garritsen, Oxana

AU - Tosoni, Giorgia

AU - Hof, Amber

AU - de Boer, Fleur

AU - van Hasenbroek, Joëlle

AU - Zhang, Lin

AU - Thrupp, Nicky

AU - Craessaerts, Katleen

AU - Fiers, Mark

AU - Salta, Evgenia

N1 - © 2024. The Author(s).

PY - 2024/9/10

Y1 - 2024/9/10

N2 - The generation of new neurons at the hippocampal neurogenic niche, known as adult hippocampal neurogenesis (AHN), and its impairment, have been implicated in Alzheimer's disease (AD). MicroRNA-132 (miR-132), the most consistently downregulated microRNA (miRNA) in AD, was recently identified as a potent regulator of AHN, exerting multilayered proneurogenic effects in adult neural stem cells (NSCs) and their progeny. Supplementing miR-132 in AD mouse brain restores AHN and relevant memory deficits, yet the exact mechanisms involved are still unknown. Here, we identify NACC2 as a novel miR-132 target implicated in both AHN and AD. miR-132 deficiency in mouse hippocampus induces Nacc2 expression and inflammatory signaling in adult NSCs. We show that miR-132-dependent regulation of NACC2 is involved in the initial stages of human NSC differentiation towards astrocytes and neurons. Later, NACC2 function in astrocytic maturation becomes uncoupled from miR-132. We demonstrate that NACC2 is present in reactive astrocytes surrounding amyloid plaques in mouse and human AD hippocampus, and that there is an anticorrelation between miR-132 and NACC2 levels in AD and upon induction of inflammation. Unraveling the molecular mechanisms by which miR-132 regulates neurogenesis and cellular reactivity in AD, will provide valuable insights towards its possible application as a therapeutic target.

AB - The generation of new neurons at the hippocampal neurogenic niche, known as adult hippocampal neurogenesis (AHN), and its impairment, have been implicated in Alzheimer's disease (AD). MicroRNA-132 (miR-132), the most consistently downregulated microRNA (miRNA) in AD, was recently identified as a potent regulator of AHN, exerting multilayered proneurogenic effects in adult neural stem cells (NSCs) and their progeny. Supplementing miR-132 in AD mouse brain restores AHN and relevant memory deficits, yet the exact mechanisms involved are still unknown. Here, we identify NACC2 as a novel miR-132 target implicated in both AHN and AD. miR-132 deficiency in mouse hippocampus induces Nacc2 expression and inflammatory signaling in adult NSCs. We show that miR-132-dependent regulation of NACC2 is involved in the initial stages of human NSC differentiation towards astrocytes and neurons. Later, NACC2 function in astrocytic maturation becomes uncoupled from miR-132. We demonstrate that NACC2 is present in reactive astrocytes surrounding amyloid plaques in mouse and human AD hippocampus, and that there is an anticorrelation between miR-132 and NACC2 levels in AD and upon induction of inflammation. Unraveling the molecular mechanisms by which miR-132 regulates neurogenesis and cellular reactivity in AD, will provide valuable insights towards its possible application as a therapeutic target.

KW - MicroRNAs/genetics

KW - Neurogenesis/genetics

KW - Alzheimer Disease/metabolism

KW - Animals

KW - Humans

KW - Neural Stem Cells/metabolism

KW - Mice

KW - Hippocampus/metabolism

KW - Astrocytes/metabolism

KW - Neurons/metabolism

KW - Cell Differentiation

KW - Gene Expression Regulation

U2 - 10.1038/s41598-024-72096-6

DO - 10.1038/s41598-024-72096-6

M3 - Article

C2 - 39256511

SN - 2045-2322

VL - 14

SP - 21163

JO - Scientific Reports

JF - Scientific Reports

IS - 1

ER -