Cholinergic neuron gene expression differences captured by translational profiling in a mouse model of Alzheimer's...

Cholinergic neurotransmission is impaired in Alzheimer's disease (AD), and loss of basal forebrain cholinergic neurons is a key component of disease pathogenicity and symptomatology. To explore the molecular basis of this cholinergic dysfunction, we paired translating ribosome affinity purification (TRAP) with RNA sequencing (TRAP-Seq) to identify the actively translating mRNAs in anterior forebrain cholinergic neurons in the TgCRND8 mouse model of AD. Bioinformatic analyses revealed the downregulation of 67 of 71 known cholinergic-related transcripts, consistent with cholinergic neuron dysfunction in TgCRND8 mice, as well as transcripts related to oxidative phosphorylation, neurotrophins, and ribosomal processing. Upregulated transcripts included those related to axon guidance, glutamatergic synapses and kinase activity and included AD-risk genes Sorl1 and Ptk2b. In contrast, the total transcriptome of the anterior forebrain showed upregulation in cytokine signaling, microglia, and immune system pathways, including Trem2, Tyrobp, and Inpp5d. Hence, TRAP-Seq clearly distinguished the differential gene expression alterations occurring in cholinergic neurons of TgCRND8 mice compared with wild-type littermates, providing novel candidate pathways to explore for therapeutic development in AD.