Recent insights from non-mammalian models of brain injuries: an emerging literature

Abstract

Traumatic brain injury (TBI) is a major global health concern and is increasingly recognized as a risk factor for neurodegenerative diseases including Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). Repetitive TBIs (rTBIs), commonly observed in contact sports, military service, and intimate partner violence (IPV), pose a significant risk for long-term sequelae. To study the long-term consequences of TBI and rTBI, researchers have typically used mammalian models to recapitulate brain injury and neurodegenerative phenotypes. However, there are several limitations to these models, including: (1) lengthy observation periods, (2) high cost, (3) difficult genetic manipulations, and (4) ethical concerns regarding prolonged and repeated injury of a large number of mammals. Aquatic vertebrate model organisms, including Petromyzon marinus (sea lampreys), zebrafish (Danio rerio), and invertebrates, Caenorhabditis elegans (C. elegans), and Drosophila melanogaster (Drosophila), are emerging as valuable tools for investigating the mechanisms of rTBI and tauopathy. These non-mammalian models offer unique advantages, including genetic tractability, simpler nervous systems, cost-effectiveness, and quick discovery-based approaches and high-throughput screens for therapeutics, which facilitate the study of rTBI-induced neurodegeneration and tau-related pathology. Here, we explore the use of non-vertebrate and aquatic vertebrate models to study TBI and neurodegeneration. Drosophila, in particular, provides an opportunity to explore the longitudinal effects of mild rTBI and its impact on endogenous tau, thereby offering valuable insights into the complex interplay between rTBI, tauopathy, and neurodegeneration. These models provide a platform for mechanistic studies and therapeutic interventions, ultimately advancing our understanding of the long-term consequences associated with rTBI and potential avenues for intervention.

Keywords: neurodegeneration; non-mammalian models; repetitive brain injury; tauopathy; traumatic brain injury.

Figure 1

The function of tau in neurons and its role in brain injury. (A) In a healthy neuron, tau plays a vital role in stabilizing and supporting axonal transport by binding to microtubules and suppressing microtubule depolymerization (81, 82). The phosphorylation state of tau influences its binding affinity to the microtubule with hypophosphorylation supporting a tighter bind (33, 83, 84). (B) Brain injury triggers various cascades, leading to the hyperphosphorylation of tau by protein kinases (85). This hyperphosphorylated state disrupts the binding of tau to microtubules, causing microtubule instability and depolymerization (33, 83, 84). Consequently, tau undergoes filamentous aggregation, forming pathognomonic lesions characteristic of chronic traumatic encephalopathy (CTE), such as neurofibrillary tangles (86). Image created using BioRender.com.

Figure 2

Splicing variants of tau. Tau undergoes alternative splicing involving exons 2, 3, and 10, resulting in six different isoforms of the protein containing the presence or absence of exons containing microtubule-binding domains (R) and N-terminal insertions (N) (87). The ratio of the different tau isoforms varies in different regions of the brain and during different stages of development (88). Tau isoform composition also varies in tauopathic diseases, such as CTE and Alzheimer’s disease, which may impact aggregation and pathology (89). Image created using BioRender.