Identifying Common Underlying Mechanisms Driving Synaptic Deficits Between TBI and AD
Abstract
The long- and short-term effects of traumatic brain injury (TBI), particularly those resulting from multiple mild-moderate concussions, are associated with pathological cascades that extend beyond the site and time of initial injury. While our knowledge of the adverse consequences associated with TBI are increasing, there is still little understanding of how the short-term effects of a TBI can lead to the increased likelihood (2- to 4-fold) of developing Alzheimer s disease (AD)-like dementia years after the initial injury. This in part reflects our limited understanding of the sustained cellular signaling deficits that remain after the initiating injury has subsided. Therefore, the objective of this study is to identify common neuronal pathogenic mechanisms that underlie the damage initiated soon after the initial injury(ies) and the sustained pathological cascades that accelerate the transition to dementia. The impact of this research will be twofold - it will elucidate early and sustained pathogenic mechanisms initiated with TBI that are known to be central to AD, and identify novel targets that can serve as the basis for developing effective treatment regimens to diminish the physical and cognitive deficits that accrue over time. There are likely several parallel maladaptive cascades that are recruited soon after TBI occurrence, but in terms of identifying common pathogenic signaling pathways that can generate similar downstream phenotypes and memory deficits, the primary "common denominator" is a dysregulation in intracellular calcium signaling that results in a sustained increase in calcium release from intracellular stores. This pathway is similarly recruited in TBI and AD, and offers a novel target for both neuroprotection soon after injury and sustained therapy to prevent progression to dementia. Around the time of injury, there is a marked influx of calcium from the extracellular space through neuronal plasma membrane channels. This in turn augments calcium release from intracellular stores within the cell, such as the endoplasmic reticulum (ER), through specific release channels (IP3 receptors and ryanodine receptors). Activation of these channels is especially problematic under this scenario, since they are triggered by calcium itself in a process termed calcium-induced calcium release and serve to propagate excessive calcium release in both time and space. Since calcium signaling is coupled to a wide array of functions fundamental to neuronal signaling, including gene transcription, synaptic transmission, long term plasticity (which encodes memory), and cell death pathways, sustained upregulation of this signaling factor has the potential to initiate, support, and sustain the immediate, short-term, and long-term pathology associated with TBI, and independently, can lead an AD-like condition. Therefore, the association between endoplasmic reticulum ER calcium dysregulation in TBI and AD is not surprising and can explain a great deal about the marked increase in the likelihood of developing dementia in TBI patients. Our hypothesis is that repeated mild TBI seeds AD/dementia by initially generating, and then sustaining, one of the core proximal pathogenic mechanisms associated with AD – namely dysregulated intracellular Ca2+. We will test this with the following Aims: Aim 1. Track and compare the progression of histopathology generated by closed-head TBI in control and AD mouse models over time. The progression of TBI-induced histopathology will be tracked using in vivo imaging of dense core plaques and labeling of histopathological markers and synaptic degradation. Aim 2. Define Ca2+ and synaptic signaling deficits in NTg and AD mice exposed to TBI. Ca2+ signaling pathways will be measured using imaging of neurons in acute brain slices. In parallel, synaptic transmission/plasticity responses will be measured and compared. Aim 3. Demonstrate behavioral deficits associated with cortical and hippocampal-
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810535
Entities
People
- Grace Stutzmann
Organizations
- Rosalind Franklin University of Medicine and Science
- United States Army