Adult Neuronal Expression of the Alzheimer Risk Protein CD2AP is Enriched in NGF-Responsive Basal Forebrain Neurons, where it Collocates with Rab-5 Endosomes

Abstract

Genome-wide association studies (GWAS) with multiple human populations have uncovered single nucleotide variants of the CD2AP gene locus that are associated with Alzheimers Disease (AD) risk. However, the role of CD2AP in AD pathogenesis remains unknown. In adult PNS neurons, previous work demonstrated that CD2AP functions as a docking-scaffold/adaptor protein coordinator of nerve growth factor (NGF) trophic signaling and RAB5-mediated endocytosis. In the adult CNS, whereas CD2AP is robustly expressed in non-neuronal cells and neurovasculature, neuronal expression is restricted and poorly characterized. In this study using publicly available single cell/nucleus RNA sequencing, we observed that CD2AP mRNA is enriched in a population of TrkA-expressing cholinergic neurons of the adult mouse basal forebrain. Immunohistology using brain tissue from adult choline acetyltransferase (ChAT) GFP reporter mice, confirmed enrichment of CD2AP protein in cholinergic projections, and in neuron soma in the diagonal band of Broca where it co-localized with RAB5. Together with previous studies from NGF-responsive PNS primary sensory neurons, these observations indicate that CD2AP may play a role in retrograde trophic signaling in NGF- responsive CNS cholinergic neurons. In addition, we observed that CD2AP expression in these soma was increased in aged mice (18-month-old), concomitant with a reduction of co-localization with RAB5, suggesting a potential role for CD2AP in aging-associated changes in retrograde trophic signaling in these neurons. Basal forebrain cholinergic neurons project to the hippocampus and cortex, are required for learning and memory, are critical for brain health during aging, and disruption of RAB5 mediated endocytosis in these neurons is central to the pathogenesis of Alzheimers disease (AD). Future studies are therefore warranted to determine if CD2AP risk variants impact endocytosis and trophic signaling in cholinergic neurons in healthy aging and/or AD.