A Lack of Amyloid β Plaques Despite Persistent Accumulation of Amyloid β in Axons of Long‐Term Survivors of Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) is a risk factor for developing Alzheimer's disease (AD).Additionally, TBI induces AD-like amyloid β (Aβ) plaque pathology within days of injury potentially resulting from massive accumulation of amyloid precursor protein (APP) in damaged axons. Here, progression of Aβ accumulation was examined using brain tissue from 23 cases with post-TBI survival of up to 3 years. Even years after injury, widespread axonal pathology was consistently observed and was accompanied by intra-axonal co-accumulations of APP with its cleavage enzymes, beta-site APP cleaving enzyme and presenilin-1 and their product, Aβ. However, in marked contrast to the plaque pathology noted in short-term cases post TBI, virtually no Aβ plaques were found in long-term survivors. A potential mechanism for Aβ plaque regression was suggested by the post-injury accumulation of an Aβ degrading enzyme, neprilysin. These findings fail to support the premise that progressive plaque pathology after TBI ultimately results in AD.

Therapy Development for Diffuse Axonal Injury

“…1,3,22,23,25 These observations suggest that TBI can induce insidiously progressive and long-term degeneration of white matter axons. Indeed, relatively selective atrophy of the white matter is a common neuroimaging finding years after TBI.…”

“…2). [23][24][25]44,54 Thus, multiple phenotypes of swollen axonal profiles may be found at the same time, representing a wide range in the size of swellings, the number of swellings along individual axons, and progressive stages evolving towards disconnection and degeneration. In many cases, the type of swollen profile is difficult to determine.…”

“…1). 3,14,[21][22][23][24][25][26] Characteristics and Progression of Axonal Pathology in DAI After TBI, two general forms of axonal pathology appear. 26 Originally referred to as retraction bulbs, single spheroids/swellings were found at the disconnected ends of axons.…”

Mild Traumatic Brain Injury and Diffuse Axonal Injury in Swine

“…Specifically, swellings in the form of discrete axonal bulbs and axonal varicosities were observed in the roots of the gyri, at the interface of the grey and white matter, and within the deep white matter. These profiles were observed in a wide range of shapes and sizes, identical to the character of traumatic axonal pathology found in humans with TBI (Adams et al, 1989;Chen et al, 2009;Grady et al, 1993;Povlishock et al, 1983;Uryu et al, 2007). (A and B), parietal (C and D), and medulla (E and F) regions of the brain.…”

“…In addition, increased intra-axonal calcium concentrations may activate proteases that can initiate or further damage the axon cytoskeleton. Moreover, these pathological processes may induce persistent changes in many traumatically injured axons, as is suggested by the observation that axonal swelling and disconnection can occur even months and years after moderate and severe TBI (Chen et al, ,2009.…”