Figure 3.
Schematic representation of the proposed mechanism by which TBI induced increases in Aβ create a vicious neurotoxic cascade leading to chronic neurodegeneration. Soluble Aβ levels are increased both clinically and experimentally following TBI and are known to impair synaptic plasticity and hence cognitive function by inhibiting LTP and enhancing LTD mechanisms of memory formation. The increased Aβ observed following TBI presumably occurs through a combination of increased generation and impaired clearance mechanisms. BACE1 levels are elevated following experimental TBI and directly contribute to the observed increases in Aβ. Caspase-3 mediated cleavage of BACE1 interacting adaptor proteins GGA1 and GGA3 has been demonstrated to modulate BACE1 levels and Aβ production following experimental TBI. The increased Aβ levels observed due to mechanisms including caspase mediated depletion of GGA1 and GGA3 could theoretically create a vicious feed forward mechanism leading to further propagation of Aβ. In vitro evidence suggests that Aβ is capable of initiating and mediating many of the cellular injury mechanisms that lead to programmed cell death following TBI.