Controlled Cortical Impact Traumatic Brain Injury in 3xTg-AD Mice Causes Acute Intra-Axonal Amyloid-  Accumulation and Independently Accelerates the Development of Tau Abnormalities

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized pathologically by progressive neuronal loss, extracellular plaques containing the amyloid-β (Aβ) peptides, and neurofibrillary tangles composed of hyperphosphorylated tau proteins. Aβ is thought to act upstream of tau, affecting its phosphorylation and therefore aggregation state. One of the major risk factors for AD is traumatic brain injury (TBI). Acute intra-axonal Aβ and diffuse extracellular plaques occur in approximately 30% of human subjects following severe TBI. Intra-axonal accumulations of tau but not tangle-like pathologies have also been found in these patients. Whether and how these acute accumulations contribute to subsequent AD development is not known, and the interaction between Aβ and tau in the setting of TBI has not been investigated. Here, we report that controlled cortical impact TBI in 3xTg-AD mice resulted in intra-axonal Aβ accumulations and increased phospho-tau immunoreactivity at 24 hours and up to 7 days post TBI. Given these findings, we investigated the relationship between Aβ and tau pathologies following trauma in this model by systemic treatment of Compound E to inhibit γ-secrectase activity, a proteolytic process required for Aβ production. Compound E treatment successfully blocked post-traumatic Aβ accumulation in these injured mice at both time points. However, tau pathology was not affected. Our data support a causal role for TBI in acceleration of AD-related pathologies, and suggest that TBI may independently affect Aβ and tau abnormalities. Future studies will be required to assess the behavioral and long-term neurodegenerative consequences of these pathologies.

Dendritic Spine Loss and Chronic White Matter Inflammation in a Mouse Model of Highly Repetitive Head Trauma

“…This rationale also holds true for the lack of an increase in Ab, or a shift in solubility of Ab, after 30 rmTBIs. We, and others, have previously shown that the abnormal production of Ab after TBI occurs at sites of axonal injury, 23,59,62 and in the absence of APP-positive varicosities, it is unlikely that Ab is being produced in higher amounts in our 3xTg-AD mice.…”

“…However, multiple groups, including ours, have reported acute increases in phosphorylated (phospho-tau) epitopes after a single TBI, including after controlled cortical impact in tau transgenic mice 58,59 and blast injury in wild-type mice. 60 Chronic hyperphosphorylation of tau has been reported at a single tau epitope in APP transgenic mice at 3 months after closed-head injury.…”

“…We did not see any APP accumulation in our mice. Because the acute increases in phospho-tau appear to occur primarily in traumatically injured axons, 58,59 this difference between the level of axonal injury might explain why we do not see changes in phospho-tau in our mice. This rationale also holds true for the lack of an increase in Ab, or a shift in solubility of Ab, after 30 rmTBIs.…”

Lifelong behavioral and neuropathological consequences of repetitive mild traumatic brain injury

“…This is common to preclinical mTBI models, as mTBI‐dependent tau pathology has been difficult to model 48. This could be due to differences in injury models,49 injury severity,50 injury frequency,15 age51 at exposure, species used (pig, rat, mice, gerbil), and genetic background (e.g., whether the animal is expressing wild type or human (or mutant) tau or amyloid). In a recent review, we discussed the current literature and the difficulties and challenges of developing in vivo TBI experimental paradigms to explore the link between repetitive head trauma with a focus on tau‐dependent changes 48.…”

Administration of COG1410 Reduces Axonal Amyloid Precursor Protein Immunoreactivity and Microglial Activation after Controlled Cortical Impact in Mice

“…The optical fractionator technique was used to count a systematic random sample of positively-stained axonal varicosities over the entire rostral to caudal extent of the region of interest. Details of these stereological methods have been previously described (Mac Donald et al, 2007a,2007bShitaka et al, 2011;Tran et al, 2011). In brief, for quantification of APP-stained axonal varicosities and Iba1-stained microglia, the region of the corpus callosum and external capsule from each coronal slice was outlined at low power (4 · ), followed by systematic counts of objects of interest at high power (60 · , oil immersion), of sites within the counting region randomly chosen by the StereoInvestigator software.…”