Transcriptomic and proteomic characterization of the locus coeruleus in a rat model of Alzheimer’s disease

• DOI: 10.1002/alz.075403
• Publication Date: 2023-12-25T10:48:41Z
• Authors: Michael Kelberman; Katharine McCann; Cheyenne D Hurst; Duc M. Duong; Alexia Marriott; Nicholas T Seyfried; David Weinshenker
• Keywords: Locus coeruleus; Forebrain

Abstract Background The noradrenergic locus coeruleus (LC) is the first region to accumulate hyperphosphorylated tau pathology (p‐tau) in Alzheimer’s disease (AD). Using TgF344‐AD transgenic rats, which develop endogenous p‐tau LC prior forebrain regions, we have recently demonstrated age‐dependent effects of on firing rates. Specifically, neurons exhibit early hyperactivity followed by late hypoactivity. These changes rates are coincident with emergence behavioral phenotypes that characterize different stages AD (neuropsychiatric symptoms cognitive deficits). Here, sought identify molecular mechanisms could contribute these using RNAscope and proteomics rats. Methods 32 male female rats wild‐type (WT) littermates aged 6 15 months were used for this study. Brains flash‐frozen isopentane dry ice stored at ‐80°C until being sectioned. At level LC, left hemisphere was collected a 1 mm tissue punch. Punches cerebellum taken as control verify enrichment brainstem punches. right sectioned 16 µm processing fluorescent situ hybridization Multiplex Fluorescent V2 Assay according manufacturer’s protocol. Probes included markers (tyrosine hydroxylase, norepinephrine transporter) those influence activity (α2‐adrenergic receptors, GRIA2, GRIN, ADCYAP1R1). Separately, punches submitted Emory Integrated Proteomics Core label‐free quantification proteins. Results revealed no differences transcript levels either age. Similarly, there α2‐adrenergic GRIA, or ADCYAP1R1 age, GRIN 6‐month animals. We observed an increase mRNA 15‐month animals, suggesting upregulation excitatory neurotransmission. Conclusions Noradrenergic neuronal identity remains in‐tact up timepoint when cell death also uncovered potential compensatory mechanism maintain disease. analysis other may affect ongoing.