Aberrant miR-339-5p/neuronatin signaling causes prodromal neuronal calcium dyshomeostasis in mutant presenilin mice
Hao-Yu Zou, … , Nan-Jie Xu, Suya Sun
Hao-Yu Zou, … , Nan-Jie Xu, Suya Sun
Published April 15, 2022
Citation Information: J Clin Invest. 2022;132(8):e149160. https://doi.org/10.1172/JCI149160.
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Aberrant miR-339-5p/neuronatin signaling causes prodromal neuronal calcium dyshomeostasis in mutant presenilin mice

Abstract

Mushroom spine loss and calcium dyshomeostasis are early hallmark events of age-related neurodegeneration, such as Alzheimer’s disease (AD), that are connected with neuronal hyperactivity in early pathology of cognitive brain areas. However, it remains elusive how these key events are triggered at the molecular level for the neuronal abnormality that occurs at the initial stage of disease. Here, we identify downregulated miR-339-5p and its upregulated target protein, neuronatin (Nnat), in cortex neurons from the presenilin-1 M146V knockin (PSEN1-M146V KI) mouse model of familial AD (FAD). Inhibition of miR-339-5p or overexpression of Nnat recapitulates spine loss and endoplasmic reticulum calcium overload in cortical neurons with the PSEN1 mutation. Conversely, either overexpression of miR-339-5p or knockdown of Nnat restores spine morphogenesis and calcium homeostasis. We used fiber photometry recording during the object-cognitive process to further demonstrate that the PSEN1 mutant causes defective habituation in neuronal reaction in the retrosplenial cortex and that this can be rescued by restoring the miR-339-5p/Nnat pathway. Our findings thus reveal crucial roles of the miR-339-5p/Nnat pathway in FAD that may serve as potential diagnostic and therapeutic targets for early pathogenesis.

Authors

Hao-Yu Zou, Lin Guo, Bei Zhang, Si Chen, Xin-Rong Wu, Xian-Dong Liu, Xin-Yu Xu, Bin-Yin Li, Shengdi Chen, Nan-Jie Xu, Suya Sun

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Figure 2

Nnat levels are increased in RSC of AD mice and patients.

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Nnat levels are increased in RSC of AD mice and patients. (A) Left: repr...
(A) Left: representative images of Nnat distribution by immunostaining in 2-month-old WT and KI mouse brain slices. White dotted lines indicate the RSC region that shows elevated levels of Nnat expression. Scale bar: 500 μm. Right: quantification of fold change of fluorescence (KI/WT) in different brain regions. n = 3 mice for each group. S1BF, primary somatosensory cortex, barrel field; VPM, ventral posteromedial thalamic nucleus; CA1, field of CA1 of HPC; CA3, field of CA3 of HPC; DG, dentate gyrus of HPC. (B) Nnat levels detected by Western blot in different brain regions of 2- to 3-month-old WT and KI mice. n = 6 mice for every group. (C) Nnat protein levels were elevated in RSC and FC of AD patients. n = 3 subjects for each group. (D) Immunostaining of Nnat and Neurotrace showed elevated Nnat+ neuron numbers and larger Nnat clusters in RSC of AD patients’ slices compared with control subjects’ slice. n = 3 subjects for each group. Arrowheads indicate the representative neurons magnified in lower right parts. Scale bars: 10 μm. All Western blot analysis of Nnat only calculated the α bands. Data are represented as mean ± SEM.*P < 0.05; **P < 0.01. Unpaired t test (B–D) and 2-way ANOVA (A) were used.