Walker KR, Kang EL, Whalen MJ, Shen Y, Tesco G.
Depletion of GGA1 and GGA3 mediates postinjury elevation of BACE1.
J Neurosci. 2012 Jul 25;32(30):10423-37.
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The question is unresolved as to whether repetitive mild traumatic brain injury (TBI) causes little bursts of Aβ that initiate and propagate tauopathy in young hosts, but then the Aβ is cleared away by the time they die. The conundrum is that 1) if you look at craniectomy tissue follow TBI, you can find diffuse Aβ deposits within hours to days, and 2) ApoE4 modulates both AD and chronic traumatic encephalopathy, yet ApoE4 is not thought to act on tauopathy directly. I believe the best model may be repetitive puffs of toxic Aβ oligomers that drive the tauopathy and are cleared by the time of death.
Tesco and her colleagues have previously shown that GGA3 regulates cellular trafficking and stability of BACE1. This study, using mice deficient in either GGA1 or GGA3, further extends the earlier observations. More importantly, they provide compelling evidence that traumatic brain injury (TBI) causes elevation of neuronal BACE1, even when GGA3 is haploinsufficient. TBI is known to induce caspase activation, which in turn leads to reduced GGA3 levels. Results from this study suggest that inhibition of BACE1 activity may prevent TBI-induced abnormal elevation of Aβ in neurons. Potentially, acute administration of BACE1 inhibitors to TBI patients may well be considered in future drug discovery.
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