The Role of Astrocyte-Derived Tau Oligomers in Neurodegeneration Triggered by TBI
Abstract
Cerebrovascular pathology is a key element in traumatic brain injury (TBI) and could represent a mechanistic link for the development of dementia after TBI. Cerebrovascular consequences of TBI include alterations in blood–brain barrier disruption and reactive astrogliosis. Astrocytes are early responders to TBI and have an essential role in stimulating other cellular responses. Different forms of reactive astrocytes have a critical role in a variety of post-trauma mechanisms including regulation of inflammation and synaptic functions. Interestingly, tau pathology has been observed in astrocytes in perivascular areas on TBI patients. Glial pathology is often found alongside neuronal tau neurofibrillary tangles (NFTs). Astrocytic tau pathology occurs in several tauopathies, such as Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), and Pick’s disease (PiD). The implication of astrocytic tau in neurodegenerative progression is unknown. Still, it has been shown that tau pathological lesions impact astrocytes function leading to deleterious consequences within the astrocytes as well as effects on neuronal death. In AD, studies described a spatial and temporal pattern in the appearance of tau tangles in patient brains that follows neuronal networks and correlates with cognitive decline. While still a contentious topic, there is strong evidence that supports the idea that propagation of pathological tau species occurs between neurons. Microglia and astrocytes have recently been shown to be active participants in the pathological spreading of tau. Nevertheless, the functional significance of propagated glial tau remains to be established. Studies suggest that tau pathology propagation is one of the mechanisms underlying the long-term neurodegenerative effects after TBI. The mechanism by how tau propagation in TBI subsequently triggers AD/ADRD pathogenesis is still unknown. Studies have shown how tau appears to be required for Aß to cause synaptic and cognitive deficits in AD. It was reported that complete ablation of tau prevents deficits in spatial learning and memory after repeated mild frontal impact in wild-type (WT) mice. These results support the idea that reduction of tau could ameliorate the detrimental effects responsible for the association between TBI and AD. Yet no studies have addressed the contribution of exclusively reducing astrocytic tau to reverting AD/ADRD pathogenesis linked to TBI. Therefore, based on these observations in conjunction with our preliminary data, we hypothesize that vascular damage triggered by TBI induces astrocytic-tau aggregation that subsequently promotes tau spreading throughout the brain eliciting synaptotoxicity and neurodegeneration as observed in AD and AD-related dementias. Unfortunately, there is no clear understanding of the molecular and cellular mechanisms that underlie the contribution of astrocytic-tau aggregates to neurodegeneration and dementias associated to TBI. Thus, we proposed to use a controlled cortical impact (CCI) injury model to dissect the mechanism(s) by which TBI leads to vascular damage followed by astrocytic-tau oligomers propagation and neurodegeneration. To do so, WT mice will be exposed to CCI to assess the relation of pathological tau with glial activation, vascular abnormalities, and neurodegeneration. We will then isolate astrocyte-derived tau oligomers in a two-step approach based on immunoprecipitation to establish if these oligomers induce synaptoxicity in primary neuronal cultures and if they induce synaptic impairment in brain slices. We will also inject these tau oligomers isolated from astrocytes into mice that express human tau in order to determine if these oligomers accelerate the onset of behavioral impairment and tau aggregation in vivo. Finally, we will also determine if the ablation of astrocytic tau rescues behavioral impairment, synaptotoxicity, and neurodegeneration associated to TBI. To do so, mice
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910774
Entities
People
- Cristian Lasagna-reeves
Organizations
- Indiana University – Purdue University Indianapolis
- United States Army