Repeat Mild Traumatic Brain Injury in Adolescent Rats Increases Subsequent β-Amyloid Pathogenesis

Abstract

Single moderate-to-severe traumatic brain injuries (TBIs) may increase subsequent risk for neurodegenerative disease by facilitating β-amyloid (Aβ) deposition. However, the chronic effects on Aβ pathogenesis of repetitive mild TBIs (rTBI), which are common in adolescents and young adults, remain uncertain. We examined the effects of rTBI sustained during adolescence on subsequent deposition of Aβ pathology in a transgenic APP/PS1 rat model. Transgenic rats received sham or four individual mild TBIs (rTBIs) separated by either 24- or 72-h intervals at post-natal day 35 (before Aβ plaque deposition). Animals were euthanized at 12 months of age and underwent immunohistochemical analyses of Aβ plaque deposition. Significantly greater hippocampal Aβ plaque deposition was observed after rTBI separated by 24 h relative to rTBI separated by 72 h or sham injuries. These increases in hippocampal Aβ plaque load were driven by increases in both plaque number and size. Similar, though less-pronounced, effects were observed in extrahippocampal regions. Increases in Aβ plaque deposition were observed both ipsilaterally and contralaterally to the injury site and in both males and females. rTBIs sustained in adolescence can increase subsequent deposition of Aβ pathology, and these effects are critically dependent on interinjury interval.

Repetitive head injury in adolescent mice: A role for vascular inflammation

“…9–12 Despite growing awareness of the potential dangers of mTBI in adolescence, relatively few animal studies use adolescent models to interrogate mTBI mechanisms. 13–16…”

Examining the Relationship between Concussion and Neurodegenerative Disorders: A Review on Amyotrophic Lateral Sclerosis and Alzheimer’s Disease

“…However, a sustained second-hit mTBI leads to an extended period of hypometabolism of the cerebrum that is longer, this possibly explains the heterogeneity in future risk for neurodegenerative disease in patients with repeat mTBI. 23 In animal models of repeated mTBI, novel therapeutic interventions are easily developed following a rapid insight to understanding repeated concussive injury and its pathophysiologic mechanisms. That of clinical studies in humans, however, suggests that repeated mTBI neuropathological changes evolve over a long period ranging to years, hence an expensive and complex research layout is required.…”

“…The long-term effect of mTBI on AD remains vague and sparse but studies on ex-professional footballers show an increase in predisposition to mTBI compared to the general population, that is, they have a higher probability to be diagnosed with AD and have an earlier age onset of the disease. 23 mTBI and Alzheimer's dementia have common clinical symptoms despite the fact they seem to be two disparate disease processes which affects younger and elderly people, respectively. 33 Amyloid-β (Aβ) peptides play a key role in the pathophysiology in AD.…”

“…Such injuries have also been linked with increased deposition of Aβ protein, especially at an older age when postmortem examinations are done. 23 Conclusion mTBI constitutes majority of brain injuries. However, studies have focused mostly on moderate-to-severe TBI as highlighted above with inconclusive and paucity of studies linking concussion and neurodegenerative disorders.…”

Building Good Policy From Good Science—The Case for Concussion and Chronic Traumatic Encephalopathy

“…7 Rodent models can also examine long-term (lifespan) changes more rapidly than prospective longitudinal studies in humans and therefore may offer us a preview of mechanisms to pursue and translate to our human studies. 8,9 …”