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Overexpression of novel candidate gene ameliorates dendritic simplification in hippocampal neurons from APP/PS1 mouse model of AD
Author(s) -
Verma Aditi,
Gnanabharathi Barathan,
Kumar Sunny,
Gowaikar Ruturaj,
Ramachandran Arathy,
Kommaddi Reddy Peera,
Rupanagudi Khader Valli,
Palkovits Miklos,
Renner Eva,
Csiba Laszlo,
Hortobagyi Tibor,
Bennett David A.,
Ravindranath Vijayalakshmi
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.041899
Subject(s) - hippocampal formation , entorhinal cortex , gene expression , biology , genetically modified mouse , microbiology and biotechnology , hippocampus , gene expression profiling , gene , dentate gyrus , transgene , neuroscience , genetics
Background Imaging and neuropathological studies have revealed the entorhinal cortex (EC) and hippocampus (HP) circuitry to be affected early on during Alzheimer’s disease (AD) progression. Changes in the EC‐HP circuitry also correlate with the episodic memory deficits that have been reported in AD. Using bulk RNA sequencing, we studied the gene expression changes in the EC and HP of adolescent (1‐month old) and young adult (3‐months old) APPswe/PS1ΔE9 (APP/PS1) mice. The analysis of RNA‐seq data revealed a single common gene, the expression of which was perturbed at both ages and both regions. We further studied the physiological implication of this gene in the transgenic mouse model of AD. Method Total RNA was isolated at 1 month and 3 months of age from the EC and HP of male APP/PS1 transgenic (Tg) and wild type (WT) control mice as an input for Illumina paired end sequencing. The reads were aligned to mouse genome after adapter trimming and read counts were generated and normalized using DESeq2 for differential gene expression analysis. qRT‐PCR based validation was performed for the differentially expressed genes. Over‐expression of novel candidate gene on primary hippocampal cultures from Tg and WT APP/PS1 mice was achieved using lentiviral transduction. Imaging of neurons was performed on Zeiss confocal microscope and morphometry and spine analysis was done using Neurolucida software. Result APP was found to be upregulated in both EC and HP at 1 month and 3 months of age in APP/PS1 mice, which served as a positive control. A single gene was consistently down‐regulated at both 1 and 3 months of age in both EC and HP, which was validated through qRT‐PCR. Over‐expression of this gene using lentiviral transduction on APP/PS1 Tg hippocampal neurons in vitro rescued the loss of dendritic complexity observed in these neurons but not spine loss. Finally, we show the down‐regulation of this gene in prefrontal cortex from human AD autopsy tissue as compared to controls. Conclusion In conclusion, our study identified a novel gene candidate that is involved in loss of dendritic complexity in AD pathogenesis early in the disease.