Traumatic brain injury and amyloid-β pathology: a link to Alzheimer's disease?

Abstract

Traumatic brain injury (TBI) has devastating acute effects and in many cases seems to initiate long-term neurodegeneration. Indeed, an epidemiological association between TBI and the development of Alzheimer's disease (AD) later in life has been demonstrated, and it has been shown that amyloid-β (Aβ) plaques — one of the hallmarks of AD — may be found in patients within hours following TBI. Here, we explore the mechanistic underpinnings of the link between TBI and AD, focusing on the hypothesis that rapid Aβ plaque formation may result from the accumulation of amyloid precursor protein in damaged axons and a disturbed balance between Aβ genesis and catabolism following TBI.

Figures

Figure 1. Immunohistochemical findings exploring mechanisms of amyloid-β plaque formation following traumatic brain injury

A | representative amyloid-β (Aβ) plaques (brown) found acute following a single incidence of traumatic brain injury (TBI) caused by a fall in an 18 year old male. The survival time from injury was just 10 hours. Plaques were identified using an antibody specific for Aβ. B | representative immunohistochemistry showing amyloid precursor protein (APP) (Ba), β-site-APP-cleaving enzyme (BACE) (Bb) and presenilin-1(PS-1) (Bc) co-accumulating (Bd) in the disconnected terminal of an axon, known as an axon bulb. C | Demonstration of axonal pathology using APP immunohistochemistry. APP (brown) accumulates within the tortuous varicosities along the length of damaged axons. D | Increased neprilysin immunoreactivity (brown) is also observed in damaged axons following TBI. Panel B is reproduced, with permission, from REF. 42 © (2009) International society of Neuropathology.

Figure 2. Potential mechanisms of post-traumatic amyloid-β formation and clearance

a | The mechanical forces that axons are subjected to during a traumatic event can damage axons by directly altering their structure or by initiating detrimental secondary cascades. Failure of axonal transport in these injured axons results in accumulation of multiple proteins that form swellings at their disconnected terminals known as axon bulbs. b | such protein accumulation has been demonstrated to include the enzymes necessary for the cleavage of amyloid precursor protein (APP) to amyloid-β (Aβ), including presenilin-1 (PS-1) and β-site APP-cleaving enzyme (BACE). c–d | Although the precise intracellular mechanism of Aβ genesis remains unclear, lipid rafts have been suggested to be important in allowing APP processing and thus Aβ accumulation within the axonal compartment. e–f | Injured axons that go on to degenerate and lyse will expel the accumulated Aβ into the brain parenchyma where it is at risk of aggregating into plaques. g | The enzyme that clears Aβ, neprilsyin (NeP), also accumulates in damaged axons and probably mitigates the effects of enhanced Aβ production. The balance of genesis versus catabolism will ultimately determine Aβ build-up. NeP may potentially act to clear Aβ within the axonal compartment or in the extracellular space.