# Connecting Alzheimer's Disease to Traumatic Synaptic Neurodegeneration

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $381,700

## Abstract

Alzheimer’s disease (AD) is a global public health crisis with unknown triggers and no disease modifying
therapies. Effective treatments likely must be initiated in the early phases of biological disease, well before
brain reserves of the neural substrates of cognition are depleted leading to overt clinical symptoms. These
‘preclinical’ periods and their triggering events, therefore, are highly significant areas of study. Traumatic brain
injury (TBI), the leading cause of death and disability in younger individuals (under age 45) worldwide, is also
the best-established epigenetic risk factor for AD. Once thought to be a monophasic injury, TBI is now known
to initiate a chronic neuroinflammatory and neurodegenerative process that leads through unknown
pathological mediators to dementing illnesses including AD, ADRDs, and chronic traumatic encephalopathy
(CTE). Synapse loss is a common, early finding in AD, and the strongest pathological correlate of AD-induced
dementia—even stronger than amyloid plaques or tau neurofibrillary tangles. Synaptic injury is also implicated
in TBI in humans and in animal models. Synapses are challenging to study due to their extremely small size and
admixture with 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 Nanostructure) to enable routine monitoring of synaptic health in
animal models and in humans. Our preliminary data demonstrate that delayed cortical synapse loss occurs
after diffuse, closed head, mild TBI in a mouse model, suggesting that synaptic neurodegeneration may lead to
neurological disability following TBI and sensitize the brain to subsequent AD-related synapse loss, hastening
the onset of dementia. We will characterize synaptic neurodegeneration resulting from mild TBI over the
lifespan, and determine its ability to predict neuropsychological and behavioral outcomes. We will then assess
complement activation—a component of the innate immune system that drives synapse loss in AD and is
maladaptively activated after mild TBI— as a mechanism of synaptic neurodegeneration. We will determine
whether targeting the complement pathway can improve synaptic health and improve behavioral outcomes
using genetic and clinically-translatable pharmacological interventions. Finally, we will assess the impact of
mild TBI on synaptic neurodegeneration related to amyloidosis and tauopathy, classic AD-related
neuropathological and biochemical processes. We will determine whether complement inhibition can prevent
TBI-induced potentiation of neurodegeneration in mouse models of these processes. These studies are
expected to reveal intervenable links between early brain injury and long-term neurodegeneration relevant to
the individuals at greater risk of AD and related brain disorders due to an earlier TBI. They will also further
establish i...

## Key facts

- **NIH application ID:** 10366645
- **Project number:** 1R01NS121612-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** TERRANCE T KUMMER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $381,700
- **Award type:** 1
- **Project period:** 2022-05-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10366645

## Citation

> US National Institutes of Health, RePORTER application 10366645, Connecting Alzheimer's Disease to Traumatic Synaptic Neurodegeneration (1R01NS121612-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10366645. Licensed CC0.

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