Gene Profiling of Nucleus Basalis Tau Containing Neurons in Chronic Traumatic Encephalopathy: A Chronic Effects of Neurotrauma Consortium Study

Abstract

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.

Synapsin-caveolin-1 Mitigates Cognitive Deficits and Neurodegeneration in PSAPP Mice

“…2A). Co-staining of the dendritic marker MAP2 with Cav-1 showed decreased MAP2 expression in the hippocampal CA1 subfield and cortex in PSAPP-SynRFP, similar to that observed in postmortem human brains of patients diagnosed with CTE, tauopathy, and AD [17,18]. In contrast, PSAPP-SynCav1 mice displayed increased hippocampal (Fig.…”

“…There are conflicting results regarding Cav-1 expression levels in the AD brain; while the present study and others have shown decreased Cav-1 protein and mRNA in the AD and neurodegenerative brain [17], Gaudreault et al detected increased Cav-1 protein and mRNA in the hippocampus and frontal cortex of AD brains [46]. It is well known that both astrocytes and microglia express Cav proteins [47][48][49].…”

“…The present study detected decreased hippocampal Cav-1 expression in PSAPP mice as earlier as 6 months with an associated fear learning deficit (data not shown). Considering that 9 month PSAPP mice exhibited decreased hippocampal Cav-1 expression along with learning and memory deficit, it is plausible that loss of Cav-1 expression in the hippocampus may contribute to neurodegeneration [17,52,53]. While the current study provides proof-of-concept for the neuroprotective and therapeutic potential of SynCav1 gene therapy in PSAPP mice, we are also currently testing whether SynCav1 delivery to PSAPP mice at 6 months of age can reverse learning and memory deficits at later time points.…”

“…One such gene therapy candidate is caveolin-1 (Cav-1), a MLR scaffolding protein that organizes NTRs (Trk) and neurotransmitter receptor signaling complexes in MLRs [12][13][14]. Both pre-clinical and clinical findings revealed that Cav-1 and Cav-1 associated signaling complexes (NTRs and neurotransmitter receptors) were decreased in degenerating neurons in AD, chronic traumatic encephalopathy (CTE), and amyotrophic lateral sclerosis (ALS) [15][16][17][18]. In contrast, we previously showed that neuron-targeted Cav-1 over-expression (i.e., synapsin-promoted Cav-1 or SynCav1) augmented agonist-mediated synaptic signaling (e.g., NTRs, neurotransmitter receptors) and dendritic arborization in vitro [12], preserved MLR-localized TrkB and extended life span in ALS mice [19], suggesting that alterations in Cav-1 expression affects pro-survival signaling and neuroprotection in neurodegenerative conditions .…”

Transcriptomic analysis of α-synuclein knockdown after T3 spinal cord injury in rats

“…This regulation of intracellular Ca2+ levels makes it an important mediator of learning and memory, and it relies on signal transduction involving extracellular signal-regulated kinase 1/2 (ERK 1/2) and cAMP response element binding protein (CREB) [27]. Recently, Mufson EJ et al [28] reported a decrease in the cholinergic neurotransmitter-related transcript CHRNB2 of neurons in traumatic encephalopathy, which encodes the acetylcholine receptor subunit β2. These findings are consistent with clinical pathology studies demonstrating cholinergicrelated defects in human TBI, including reduced ChAT activity and immunoreactivity, as well as downregulation of vAChT and AChE [29].…”