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Articles, Neurobiology of Disease

Depletion of GGA1 and GGA3 Mediates Postinjury Elevation of BACE1

Kendall R. Walker, Eugene L. Kang, Michael J. Whalen, Yong Shen and Giuseppina Tesco
Journal of Neuroscience 25 July 2012, 32 (30) 10423-10437; https://doi.org/10.1523/JNEUROSCI.5491-11.2012
Kendall R. Walker
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Eugene L. Kang
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Michael J. Whalen
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Yong Shen
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Giuseppina Tesco
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Abstract

Traumatic brain injury (TBI) is one of the most robust environmental risk factors for Alzheimer's disease (AD). Compelling evidence is accumulating that a single event of TBI is associated with increased levels of Aβ. However, the underlying molecular mechanisms remain unknown. We report here that the BACE1 interacting protein, GGA3, is depleted while BACE1 levels increase in the acute phase after injury (48 h) in a mouse model of TBI. We further demonstrated the role of GGA3 in the regulation of BACE1 in vivo by showing that BACE1 levels are increased in the brain of GGA3-null mice. We next found that head trauma potentiates BACE1 elevation in GGA3-null mice in the acute phase after TBI, and discovered that GGA1, a GGA3 homolog, is a novel caspase-3 substrate depleted at 48 h after TBI. Moreover, GGA1 silencing potentiates BACE1 elevation induced by GGA3 deletion in neurons in vitro, indicating that GGA1 and GGA3 synergistically regulate BACE1. Accordingly, we found that levels of both GGA1 and GGA3 are depleted while BACE1 levels are increased in a series of postmortem AD brains. Finally, we show that GGA3 haploinsufficiency results in sustained elevation of BACE1 and Aβ levels while GGA1 levels are restored in the subacute phase (7 d) after injury. In conclusion, our data indicate that depletion of GGA1 and GGA3 engender a rapid and robust elevation of BACE1 in the acute phase after injury. However, the efficient disposal of the acutely accumulated BACE1 solely depends on GGA3 levels in the subacute phase of injury.

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The Journal of Neuroscience: 32 (30)
Journal of Neuroscience
Vol. 32, Issue 30
25 Jul 2012
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Depletion of GGA1 and GGA3 Mediates Postinjury Elevation of BACE1
Kendall R. Walker, Eugene L. Kang, Michael J. Whalen, Yong Shen, Giuseppina Tesco
Journal of Neuroscience 25 July 2012, 32 (30) 10423-10437; DOI: 10.1523/JNEUROSCI.5491-11.2012

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Depletion of GGA1 and GGA3 Mediates Postinjury Elevation of BACE1
Kendall R. Walker, Eugene L. Kang, Michael J. Whalen, Yong Shen, Giuseppina Tesco
Journal of Neuroscience 25 July 2012, 32 (30) 10423-10437; DOI: 10.1523/JNEUROSCI.5491-11.2012
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