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Aberrant miR-339-5p/neuronatin signaling causes prodromal neuronal calcium dyshomeostasis in mutant presenilin mice
- Source :
- Journal of Clinical Investigation. April 15, 2022, Vol. 132 Issue 8
- Publication Year :
- 2022
-
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-M146VKI) 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.<br />Introduction Alzheimer's disease (AD) is one of the most prevalent age-related neurodegenerative disorders and is characterized by progressive memory impairment and cognitive deficits, often manifested pathologically by the deposition of [...]
- Subjects :
- Neurons -- Health aspects -- Physiological aspects
Calcium metabolism -- Research
Homeostasis -- Research
Chromosomal proteins -- Health aspects -- Physiological aspects
MicroRNA -- Health aspects -- Physiological aspects
Neurological research
Alzheimer's disease -- Development and progression -- Genetic aspects
Cellular signal transduction -- Research
Health care industry
Subjects
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 132
- Issue :
- 8
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.701600098
- Full Text :
- https://doi.org/10.1172/JCI149160