Spatiotemporal characterization of disease-associated neurons in the entorhinal cortex-hippocampal circuit during Alzheimer’s disease progression

The entorhinal cortex (EC)-hippocampal (HPC) circuit is particularly vulnerable to Alzheimer’s disease (AD) pathology, yet the underlying molecular mechanisms remain unclear. By employing the high-depth sequencing strategy Smart-seq2, we tracked gene expression changes across various neuron types within this circuit at different stages of AD pathology. We observed a decrease in the extent of gene expression changes in AD versus wild-type (WT) mice as the disease advanced. Functionally, we demonstrate that both mitochondrial and ribosomal pathways were increasingly activated, while neuronal pathways were inhibited with AD progression. Our findings indicate that the reduction of EC-stellate cells disrupts Meg3-mediated energy metabolism, contributing to energy dysfunction in AD. Additionally, we identified GFAP-positive neurons as a distinct population of disease-associated neurons, exhibiting a loss of neuronal-like characteristics, alongside the emergence of glia- and stem-like features. The number of GFAP-positive neurons increased with AD progression, a trend consistently observed in both AD model mice and AD patients. In summary, this study identifies and characterizes GFAP-positive neurons as a novel subtype of disease-associated neurons in AD pathology, providing insights into their potential role in disease progression.