Impact of RTN3 Deficiency on Expression of BACE1 and Amyloid Deposition

Abstract

Reticulon 3 (RTN3) has previously been shown to interact with BACE1 and negatively regulate BACE1 activity. To what extent RTN3 deficiency affects BACE1 activity is an intriguing question. In this study, we aimed to address this by generating RTN3-null mice. Mice with complete deficiency of RTN3 grow normally and have no obviously discernible phenotypes. Morphological analyses of RTN3-null mice showed no significant alterations in cellular structure, although RTN3 is recognized as a protein contributing to the shaping of tubular endoplasmic reticulum. Biochemical analysis revealed that RTN3 deficiency increased protein levels of BACE1. This elevation of BACE1 levels correlated with enhanced processing of amyloid precursor protein at the ␤-secretase site. We also demonstrated that RTN3 deficiency in Alzheimer's mouse models facilitates amyloid deposition, further supporting an in vivo role of RTN3 in the regulation of BACE1 activity. Since it has been shown that RTN3 monomer is reduced in brains of Alzheimer's patients, our results suggest that long-lasting reduction of RTN3 levels has adverse effects on BACE1 activity and may contribute to Alzheimer's pathogenesis.

Inhibiting BACE1 to reverse synaptic dysfunctions in Alzheimer’s disease

“…Altering trafficking of BACE1 in secretory compartments is therefore another strategy to reduce or enhance BACE1 activity (Jiang et al, 2014; Tan and Evin, 2012; Vassar et al, 2014). For instance, enhanced retention of BACE1 by an ER protein such as RTN/Nogo in the ER can significantly reduce BACE1 cleavage of APP, thereby decreasing Aβ production (Araki et al, 2012; Deng et al, 2013; He et al, 2004; Shi et al, 2014; Shi et al, 2009; Shi et al, 2013; Wojcik et al, 2007). 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.…”

BAP31 deficiency contributes to the formation of amyloid‐β plaques in Alzheimer's disease by reducing the stability of RTN3

“…RTN3 is a negative modulator of BACE1 activity, and RTN3 deficiency can increase the protein levels of BACE1 (10). Therefore, the protein levels of BACE1 were examined; when BAP31 was overexpressed, BACE1 was decreased significantly in SH‐SY5Y695 cells ( Fig.…”

“…RTN proteins are a group of integral membrane proteins associated predominantly with the ER (23, 24). RTN3 and its family of proteins were initially identified as modulators of BACE1 because they create a spatial hindrance that prevents BACE1 from gaining access to its APP substrate for catalytic cleavage (10, 25, 26). However, RTN3 is a protein that easily aggregates, and the over‐expression of RTN3 alone, even by only 1‐fold, is sufficient to provoke the formation of RTN3 aggregation and RIDNs within the brains of Tg‐RTN3 mice, which reduces the available RTN3 monomer and aggravates APs deposition (12).…”

“…High BACE1 expression and activity in the post mortem brains and cerebrospinal fluid of AD patients have been found (32), and RTN3 plays a role in decreasing the protein levels of BACE1 (10). However, the mechanism is not yet clear.…”

“…The proteins of the reticulon (RTN) family (RTN1-RTN4) are largely regarded as membrane-bound proteins that shape the tubular networks of the endoplasmic reticulum (ER). Neuronal-enriched RTN3 has been identified as a negative modulator of BACE1 (3,(9)(10)(11). However, RTN3 easily forms high MW (HMW)-RTN3 aggregates, which accumulated in a distinct population of dystrophic neurites (DNs) named RTN3 immunoreactive DNs (RIDNs) (12).…”