# Imaging Synaptic Injury in TBI using SEQUIN

> **NIH VA I01** · ST. LOUIS VA MEDICAL CENTER · 2022 · —

## Abstract

Traumatic brain injury (TBI) is the leading cause of death and disability in adults under the age of 45, affecting
∼20% of veterans from recent wars. Once thought to be a monophasic injury, TBI is now known to trigger an
indolent neurodegenerative process that substantially increases the risk of Alzheimer’s and other forms of
dementia for older veterans. All disability resulting from TBI stems from its disruption of functional neural
networks. The mechanisms by which TBI interrupts these networks and sets up further neurodegenerative
network breakdown are inadequately defined, though injury loci beyond those observed in white matter are
increasingly recognized. Synaptic injury has been identified following TBI in humans and in animal models,
resulting in pathological molecular, structural, and functional changes to synapses, or their frank loss. Synapse
loss is also a common, early finding in Alzheimer’s disease (AD) where it is the strongest pathological correlate
of AD-induced dementia—even stronger than amyloid plaques or tau tangles. Neuroinflammatory pathways
are activated in a prolonged fashion after TBI in animal models and in humans, and play a central role in
mediating synapse loss in AD. A better understanding of synaptic injury in TBI, and its neuroinflammatory
mediators, therefore, could supply a missing and potentially interruptible structural-mechanistic connection
between these conditions. Synapses, however, are very challenging to study due to their extremely small size
and admixture within the extraordinarily complex subcellular milieu of mammalian neuropil. We developed an
innovative, widely accessible super-resolution imaging and image analysis platform called SEQUIN (Synaptic
Evaluation and QUantification by Imaging of Nanostructure) to enable routine monitoring of synaptic health in
animal models and in humans. Our preliminary data demonstrate that synapse loss is a prominent feature of
diffuse, closed head TBI in a militarily-relevant mouse model, and indicate that inhibition of the complement
pathway (part of the innate immune system) prevents traumatic synapse loss and improves function after TBI.
These findings suggest that neuroinflammatory synaptic injury leads to acute neurological disability following
diffuse TBI and sensitizes the brain to subsequent neurodegenerative changes, hastening the onset of
dementia. We propose to first (Aim 1) characterize regional synapse loss resulting from diffuse TBI and
determine its neuropsychological and behavioral correlates at a scale impossible to achieve pre-SEQUIN. We
will then (Aim 2) determine the role of the complement pathway in mediating traumatic synapse loss, and
determine whether genetic and/or pharmacological targeting of this pathway can rescue synaptic endpoints
and improve functional outcomes. Lastly, we will (Aim 3) determine whether and how TBI potentiates synapse
loss later in life in response to the amyloid- and tau-related neurodegeneration that typifies AD. The...

## Key facts

- **NIH application ID:** 10347182
- **Project number:** 5I01BX005204-02
- **Recipient organization:** ST. LOUIS VA MEDICAL CENTER
- **Principal Investigator:** TERRANCE T KUMMER
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-10-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10347182

## Citation

> US National Institutes of Health, RePORTER application 10347182, Imaging Synaptic Injury in TBI using SEQUIN (5I01BX005204-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10347182. Licensed CC0.

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