Subacute Changes in Cleavage Processing of Amyloid Precursor Protein and Tau following Penetrating Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) is an established risk factor for the development of Alzheimer’s disease (AD). Here the effects of severe penetrating TBI on APP and tau cleavage processing were investigated in a rodent model of penetrating ballistic-like brain injury (PBBI). PBBI was induced by stereotactically inserting a perforated steel probe through the right frontal cortex of the anesthetized rat and rapidly inflating/deflating the probe’s elastic tubing into an elliptical shaped balloon to 10% of total rat brain volume causing temporary cavitation injury. Separate animals underwent probe injury (PrI) alone without balloon inflation. Shams underwent craniectomy. Brain tissue was collected acutely (4h, 24h, 3d) and subacutely (7d) post-injury and analyzed by immunoblot for full length APP (APP-FL) and APP beta c-terminal fragments (βCTFs), full length tau (tau-FL) and tau truncation fragments and at 7d for cytotoxic Beta amyloid (Aβ) peptides Aβ40 and Aβ42 analysis. APP-FL was significantly decreased at 3d and 7d following PBBI whereas APP βCTFs were significantly elevated by 4h post-injury and remained elevated through 7d post-injury. Effects on βCTFs were mirrored with PrI, albeit to a lesser extent. Aβ40 and Aβ42 were significantly elevated at 7d following PBBI and PrI. Tau-FL decreased substantially 3d and 7d post-PBBI and PrI. Importantly, a 22 kDa tau fragment (tau22), similar to that found in AD, was significantly elevated by 4h and remained elevated through 7d post-injury. Thus both APP and tau cleavage was dramatically altered in the acute and subacute periods post-injury. As cleavage of these proteins has also been implicated in AD, TBI pathology shown here may set the stage for the later development of AD or other tauopathies.

Penetrating Ballistic-Like Brain Injury Leads to MicroRNA Dysregulation, BACE1 Upregulation, and Amyloid Precursor Protein Loss in Lesioned Rat Brain Tissues

“…In this case, APP is cleaved by β-secretase to release sAPPβ and CTF99, then the γ-secretase complex, cleaves CTF99 to generate Aβ-40/-42 (Cole and Vassar, 2008). Our lab previously indicated that APP loss occurs during subacute PBBI (Cartagena et al, 2016). Therefore, the results presented herein suggest that miRNAs may be coordinated with APP cleavage through enzymes during acute-subacute TBI progression.…”

Moderate blast exposure alters gene expression and levels of amyloid precursor protein

“…APP has been well established as being elevated in the brain acutely after biTBIs, 6 – 10 as well as blunt force TBIs in preclinical models and penetrating injuries in military personnel. 11 , 12 However, it has been posited that APP plays a neuroprotective role after TBI. 13 Traditionally, the ubiquitously expressed APP has been considered a marker of axonal injury, known to increase after TBI and to relate to the severity of neuronal injury.…”

The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease

“…Both Aβ40 and Aβ42 were increased at 7 DPI, but the authors explain that detection was difficult due to low expression. Similarly, full length tau decreased at 3 and 7 DPI but oligomeric tau was elevated at 4 h and 7 DPI ( 188 ). Out of these studies, only one reported that increased Aβ and tau pathology occurred in conjunction with neuronal loss and increased MHC-II immunoreactivity several months post-injury ( 177 ).…”