Neuronal gene profiling of tau oligomer-bearing cholinergic nucleus basalis neurons during the onset of Alzheimer’s disease

Soluble tau oligomeric assemblies display neurotoxic properties and may provide a pathogenic link between neurofibrillary tangle evolution and selective neuronal vulnerability in Alzheimer's disease (AD). However, the precise molecular and cellular pathways mediating tau oligomer toxicity are unclear. We combined single-neuron laser capture microdissection with custom microarrays to investigate differences in the molecular signatures of basal forebrain neurons within the nucleus basalis of Meynert (nbM) labeled for p75^NTR, a cholinergic cell marker, or dual-labeled for p75^NTR and TOC1, a tau oligomer marker. Tissue was obtained postmortem from Rush Religious Orders Study participants who died with an antemortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), or mild/moderate AD. Using clinical diagnosis as a covariate to isolate tau oligomer-specific mechanisms, we identified 140 differentially expressed genes (DEGs) in p75^NTR + /TOC1 + cholinergic nbM neurons compared to p75^NTR + /TOC1- neurons. STRING interactome and pathway analysis revealed that downregulated genes were associated with pre- and postsynaptic function, with additional enrichment in glutamate and acetylcholine signaling. By contrast, upregulated genes related to cellular stress responses and apoptosis were clustered with a subset of downregulated DEGs regulating mitochondrial metabolism and redox function, indicative of bioenergetic failure. Weighted gene co-expression correlation network analysis of the entire dataset revealed only two significantly correlated modules, which were either negatively correlated with the presence of TOC1 and enriched for synaptic signaling or positively correlated with TOC1 and enriched for cellular responses to hypoxia. These data show with single-neuron resolution that oligomeric tau formation in vulnerable cholinergic nbM neurons, even prior to MCI, is associated with the dysregulation of multiple classes of genes driving cell/mitochondrial stress and synaptic imbalances, which may be amenable for disease-modifying therapeutic approaches.