Depletion of GGA1 and GGA3 Mediates Postinjury Elevation of BACE1

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 post-injury (48hrs) 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 post-TBI and discovered that GGA1, a GGA3 homologue, is a novel caspase-3 substrate depleted at 48 hrs post-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 post-mortem 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 days) post-injury. In conclusion, our data indicate that depletion of GGA1 and GGA3 engender a rapid and robust elevation of BACE1 in the acute phase post-injury. However, the efficient disposal of the acutely accumulated BACE1 solely depends on GGA3 levels in the sub-acute phase of injury.

Inhibiting BACE1 to reverse synaptic dysfunctions in Alzheimer’s disease

“…Increased trafficking of BACE1 in the more acidic endosomes by cellular trafficking proteins such as a Vps10p domain-sorting receptor sortilin (Finan et al, 2011), the small GTPase ADP ribosylation factor 6 (ARF6) (Sannerud et al, 2011), Rab-GTPases Rab11 (Udayar et al, 2013), and Sorting nexin 12 (Zhao et al, 2012) results in significant increases in Aβ generation. Golgi-localized γ-ears containing ADP ribosylation factor-binding (GGA) family proteins can bind BACE1 via the di-leucine motif and impact not only its endosomal trafficking, but also its stability (He et al, 2002; He et al, 2005; Santosa et al, 2011; Tesco et al, 2007; von et al, 2015; Wahle et al, 2005; Walker et al, 2012). Depletion of both GGA1 and GGA3 induces a rapid and robust elevation of BACE1, and such an effect will likely be interfered with by flotillin, which can compete with GGA proteins for binding to the same dileucine motif in the BACE1 tail (John et al, 2014).…”

SEPT8 modulates β-amyloidogenic processing of APP via affecting the sorting and accumulation of BACE1

“…Thus, our biochemical and immunohistochemical findings together suggest that overexpression of SEPT8 TV3 promotes sorting and accumulation of BACE1 to the recycling or early endosomal compartments, which are optimal sites for its enzymatic activity (Tesco et al, 2007). These changes were not associated with altered protein levels of factors affecting the endosomal or intracellular trafficking of BACE1, such as Arf6, GGA1 or GGA3, or with alterations in the Lys48-or Lys63-linked ubiquitylation known to regulate the lysosomal and proteosomal trafficking of BACE1 Walker et al, 2012). Importantly, our results are in line with recent studies that have shown that BACE1 mainly accumulates in the TfR-positive endosomes and is degraded in the lysosomes (Kandalepas et al, 2013).…”

Inhibitory activities of major anthraquinones and other constituents from Cassia obtusifolia against β-secretase and cholinesterases

“…In addition, it has been reported that BACE1 activity in mouse, monkey, and human brains increases with age, which is the primary risk factor for AD (Fukumoto et al, 2004). In particular, emerging evidence shows significant elevation of BACE1 in the circumstances of other AD risk factors, such as traumatic brain injury, stroke, and cardiovascular events (Cole and Vassar, 2008;Walker et al, 2012).…”