Military personnel and athletes exposed to
traumatic brain injury may develop
chronic traumatic encephalopathy (CTE). Brain pathology in CTE includes intracellular accumulation of abnormally phosphorylated
tau proteins (p-tau), the main constituent of neurofibrillary tangles (NFTs). Recently, we found that
cholinergic basal forebrain (CBF) neurons within the nucleus basalis of Meynert (nbM), which provide the major
cholinergic innervation to the cortex, display an increased number of NFTs across the pathological stages of CTE. However, molecular mechanisms underlying nbM neurodegeneration in the context of CTE pathology remain unknown. Here, we assessed the genetic signature of nbM neurons containing the p-tau pretangle maker pS422 from CTE subjects who came to autopsy and received a neuropathological CTE staging assessment (Stages II, III, and IV) using
laser capture microdissection and custom-designed microarray analysis. Quantitative analysis revealed dysregulation of key genes in several gene ontology groups between CTE stages. Specifically, downregulation of the nicotinic
cholinergic receptor subunit β-2 gene (CHRNB2), monoaminergic
enzymes catechol-O-methyltransferase (COMT) and
dopa decarboxylase (DDC),
chloride channels CLCN4 and CLCN5, scaffolding
protein caveolin 1 (CAV1), cortical development/cytoskeleton
element lissencephaly 1 (LIS1), and intracellular signaling cascade member
adenylate cyclase 3 (ADCY3) was observed in pS422-immunreactive nbM neurons in CTE patients. By contrast, upregulation of
calpain 2 (CAPN2) and
microtubule-associated protein 2 (MAP2) transcript levels was found in Stage IV CTE patients. These single-population data in vulnerable neurons indicate alterations in gene expression associated with neurotransmission, signal transduction, the cytoskeleton, cell survival/death signaling, and microtubule dynamics, suggesting novel molecular pathways to target for drug discovery in CTE.