Distinct Transcriptional States of TDP-43 Pathology in an Alzheimer's Disease Mouse Model.

Alzheimer's disease (AD) is frequently accompanied by cytoplasmic TDP-43 inclusions, although its pathogenic role remains unclear. Using Immuno-LCM-RNAseq in hippocampal excitatory neurons from APP/PS1 mice, we characterized two distinct TDP-43 states: diffuse cytoplasmic mislocalization (Cyto+) and punctate aggregates (Aggre+). Cyto+ neurons exhibited a compensatory "pre-aggregation" signature characterized by enhanced synaptic organization and long-term potentiation pathways, along with altered nucleocytoplasmic transport, phosphorylation/proteolysis regulation, and lipid dysregulation. Aggre+ neurons showed pronounced transcriptional changes associated with neuronal hyperexcitability, including increased calcium signaling and exocytosis, together with protein polymerization and autophosphorylation, mitochondrial dysfunction, and impaired regenerative pathways. Shared features included persistent lipid dysregulation, altered ApoE signaling, and transcriptional repression. Comparison of these states revealed potential upstream therapeutic targets, including ERK1/2, PI3K, small GTPases, and mRNA splicing pathways. These findings provide a transcriptional framework linking early TDP-43 stress responses to pathological aggregation in AD.