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).