microRNA-425 loss mediates amyloid plaque microenvironment heterogeneity and promotes neurodegenerative pathologies

• Authors: Yong-Bo Hu, Shanghai Jiao Tong University; Yong-Fang Zhang, Shanghai Jiao Tong University; Ru-Jing Ren, Shanghai Jiao Tong University; Eric Dammer, Emory University; Xin-Yi Xie, Shanghai Jiao Tong University; Shi-Wu Chen, Shanghai Jiao Tong University; Qiang Huang, Shanghai Jiao Tong University; Wan-Ying Huang, Shanghai Jiao Tong University; Rui Zhang, Shanghai Jiao Tong University; Hong-Zhuan Chen, Shanghai University of Traditional Chinese Medicine; Hao Wang, Shanghai Jiao Tong University; Gang Wang, Shanghai Jiao Tong University
• Journal Title: AGING CELL
• Volume: Volume 20, Number 10
• Publisher: WILEY | 2021-09-12, Pages e13454-e13454
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1111/acel.13454
• Subjects: Chemistry, Biochemistry
• Keywords: Science & Technology; Life Sciences & Biomedicine; Cell Biology; Geriatrics & Gerontology; Alzheimer's disease; amyloid plaque; microenvironment; miR-425; neurodegeneration; oligonucleotide; ALZHEIMERS-DISEASE; BETA; TAU; PATHOPHYSIOLOGY; EXPRESSION; OLIGOMERS; INSIGHTS; NETWORK; PTEN

Abstract

Different cellular and molecular changes underlie the pathogenesis of Alzheimer's disease (AD). Among these, neuron-specific dysregulation is a necessary event for accumulation of classic pathologies including amyloid plaques. Here, we show that AD-associated pathophysiology including neuronal cell death, inflammatory signaling, and endolysosomal dysfunction is spatially colocalized to amyloid plaques in regions with abnormal microRNA-425 (miR-425) levels and this change leads to focal brain microenvironment heterogeneity, that is, an amyloid plaque-associated microenvironment (APAM). APAM consists of multiple specific neurodegenerative signature pathologies associated with senile plaques that contribute to the heterogeneity and complexity of AD. Remarkably, miR-425, a neuronal-specific regulator decreased in AD brain, maintains a normal spatial transcriptome within brain neurons. We tested the hypothesis that miR-425 loss correlates with enhanced levels of mRNA targets downstream, supporting APAM and AD progression. A miR-425-deficient mouse model has enhanced APP amyloidogenic processing, neuroinflammation, neuron loss, and cognitive impairment. In the APP/PS1 mouse model, intervening with miR-425 supplementation ameliorated APAM changes and memory deficits. This study reveals a novel mechanism of dysregulation of spatial transcriptomic changes in AD brain, identifying a probable neuronal-specific microRNA regulator capable of staving off amyloid pathogenesis. Moreover, our findings provide new insights for developing AD treatment strategies with miRNA oligonucleotide(s).