Project Title: Effects of SARS-CoV-2 on human brain

Increasing evidence supports that the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with neurological manifestations, such as impaired consciousness, headache, and neuropsychiatric disorder. A few neuropathological examinations have observed a spectrum of neuroinflammatory and hypoxic damage in post-mortem brains of COVID-19 patients. However, less is known about whether SARS-CoV-2 infection is associated with blood-brain barrier (BBB) disruption.

To address this, we will first determine the presence of SARS-CoV-2 in patients with COVID-19 using RNA fluorescence in-situ hybridization. In parallel, we will use immunohistochemical staining of fibrinogen to examine any BBB disruption. This will be done in conjunction with control patients without a history of COVID-19 and no degenerative brain diseases. This study, upon completion, will help to understand if SARS-CoV-2 infection leads to BBB disruption.

Project Title: Investigating the role of neuronal pentraxins in TBI-related neurodegeneration

Abstract: NPTX2 is a pre-synaptically secreted glycoprotein intimately linked to activity dependent synaptic activity. Upon binding to its postsynaptic receptor, NPTX2 initiates GluA4 AMPA receptor clustering. This process selectively regulates excitatory synapse assembly between pyramidal cells and GABAergic parvalbumin interneurons (PV-INs) and is the basis for fast-spiking synaptic transmission. In both Dementia with Lewy bodies (DLB) and PD, NPTX2 colocalizes with pathological aggregates of α-synuclein. In AD, NPTX2 functional loss is associated with increased burden of hyperphosphorylated tau and reduced AMPA receptor electrophysiological activity. As α-synuclein aggregation and tauopathy are common in Traumatic brain injury Related Neurodegeneration (TReND) and represent a hallmark of Chronic Traumatic Encephalopathy (CTE), this study aimed to characterize potential toxic aggregation of NPTX2 following TBI.

Project Title: Defining Hypo N-Glycosylation following TBI

Abstract: N-linked protein glycosylation is a cellular process that decorates a large number of proteins with chains of sugar molecules within the human body. The process is highly regulated and results in a unique glycan profile for each cell in the brain, with N-glycosylated proteins known to regulate key brain processes including learning and memory formation. Furthermore, aberrant N-glycosylation results in neuroinflammation and neuronal cell death. Using a mouse model of traumatic brain injury (TBI) we performed an analysis of global changes in N-linked glycans using cutting edge technology. These data demonstrate that TBI results in defects in glycosylation and suggest that dysregulation of this process could be one of the underpinnings of TBI pathophysiology. We wish to determine whether similar N-glycosylation alterations occur within the injured human brain following traumatic brain injury.

Project Title: Correlating Glycomics and Glycoproteomics Biomarker Signatures of traumatic brain injury and Alzheimer’s disease

Abstract: Will examine glycan and glycoprotein profiles across different body compartments (brain, CSF and blood) after TBI in relation to dementia.

Project Title: Sodium channel changes after concussion and TBI

Abstract: Although TBI is a major health concern, little is known about pathophysiological changes that cause post-traumatic cognitive dysfunction. Nonetheless, emerging evidence suggests that selective damage to white matter axons, or diffuse axonal injury (DAI), disrupts brain network connectivity and function. While voltage-gated sodium channels (NaChs) and their anchoring proteins at the nodes of Ranvier (NOR) on axons are key elements of the brain’s network signaling machinery, changes in their integrity have not been studied in context with DAI.

To address this, we propose to examine the changes in NaChs, Nav1.6 in particular, and associated NOR morphologies in material from patients with known history of single moderate or severe TBI. We will then compare our findings to material from age matched, non-injured controls with no known history of neurological disease. We will further employ immunofluorescent staining approach to examine the relevance of NaCh changes to DAI.

Outcome: Dr. Song successfully used this human tissue request from the CONNECT-TBI network to confirm sodium channel and Node of Ranvier changes found in an experimental concussion model of TBI.

Project Title: Single Nucleus Transcriptomics in Chronic TBI

Abstract: Moderate or severe traumatic brain injury (TBI) is a substantial health problem that In addition to often devastating acute effects, can trigger complex chronic pathologies. In a subset of individuals, progressive loss of both the grey and white matter in the brain has been observed following moderate or severe TBI, in some cases persisting many months and years after injury. However, the processes occurring that drive this chronic degeneration are unknown. By examining post-mortem brain tissue from individuals both with and without progressive degeneration after TBI, we aim to perform a detailed examination of the function of cells in the brain.

We will achieve this using single cell RNA sequencing -a technique that permits us to identify the genes that each individual cell is expressing. This will allow us to identify the specific ways in which cells in the brain degenerate over time. Understanding these processes may help elucidate potential pathways that can be targeted to prevent progressive degeneration following TBI.

Project Title: TDP-43 proteinopathy in traumatic brain injury related neurodegeneration (TReND)

Abstract: Traumatic brain injury (TBI) is a risk factor for dementia and related degenerative brain diseases. Pathology studies of the brains of people with a history of TBI show a range of abnormalities. Among these, abnormal deposition of a protein known as TDP-43 has been described. However, this abnormal TDP-43 protein can also be found in many other degenerative brain diseases. To date it remains uncertain whether the TDP-43 abnormalities in patients with TBI are unique or are simply a reflection of other, coincident pathologies.

In this study, we will investigate the pattern and distribution of TDP-43 protein deposition in patients with a history of TBI. We will then compare our findings in patients with TBI to the deposition of TDP-43 in normal aging and other degenerative brain diseases. This will give us a picture of the effect of TBI on TDP-43 deposition which might help our understanding of the link between brain injury and dementia.

Project title: Pilot study of the role of spleen tyrosine kinase in pathobiology of repetitive mild TBI

Abstract: We have identified a novel molecular target (Spleen Tyrosine Kinase, Syk) for Alzheimer’s disease, inhibition of which, by the compound Nilvadipine, results in mitigation of amyloid, tau and neuroinflammatory pathology in mouse models of Alzheimer’s disease. Nilvadipine was demonstrated to reduce Alzheimer’s cognitive decline in early stage Alzheimer’s patients in a Phase III trial. We have tested Nilvadipine in our mouse models of repetitive mild TBI and shown reduction in neuroinflammation and tau pathology, as well as improvement in cognitive outcomes. We therefore wish to determine the relevance of our findings to the human TBI patient population by determining if Syk or related Syk signaling molecules can be detected in the brains of TBI patients versus controls.