Reduced Amyloid Deposition in Mice Overexpressing RTN3 Is Adversely Affected by Preformed Dystrophic Neurites

Abstract

Reticulon 3 (RTN3) was initially identified as a negative modulator of BACE1, an enzyme that cleaves amyloid precursor protein (APP) to release ␤-amyloid peptide. Interestingly, RTN3 can also form aggregates after accumulation, and increased RTN3 aggregation correlates with the formation of RTN3 immunoreactive dystrophic neurites (RIDNs) in brains of Alzheimer's cases. Transgenic mice expressing RTN3 alone develop RIDNs in their hippocampus but not in their cortex. To determine the in vivo effects of RTN3 and preformed RIDNs on amyloid deposition, we crossed bitransgenic mice expressing APP and presenilin 1 (PS1) mutations with mice overexpressing RTN3. We found that amyloid deposition in cortex, the hippocampal CA3 region, and dentate gyrus was significantly reduced in triple transgenic mice compared with bitransgenic controls. However, reduction of amyloid deposition in the hippocampal CA1 region, where RIDNs predominantly formed before amyloid deposition, was less significant. Hence, preformed RTN3 aggregates in RIDNs clearly offset the negative modulation of BACE1 activity by RTN3. Furthermore, our study indicates that the increased expression of RTN3 could result in an alteration of BACE1 intracellular trafficking by retaining more BACE1 in the endoplasmic reticulum compartment where cleavage of APP by BACE1 is less favored. Our results suggest that inhibition of RTN3 aggregation is likely to be beneficial by reducing both amyloid deposition and the formation RIDNs.

Arabidopsis RTNLB1 and RTNLB2 Reticulon-Like Proteins Regulate Intracellular Trafficking and Activity of the FLS2 Immune Receptor

“…RTNLB1 and RTNLB2 are known to interact through their reticulon domains (Hwang and Gelvin, 2004;Sparkes et al, 2010); thus, they may function as a heterodimer or as part of a larger protein complex to regulate FLS2 secretion. Furthermore, considering the role of the human RTNs in intracellular protein trafficking (Wakana et al, 2005;He et al, 2006;Liu et al, 2008;Chang et al, 2009;Shi et al, 2009;Yang et al, 2009), our findings indicate functional conservation between RTNs and plant RTNLBs.…”

Diabetes-induced Central Neuritic Dystrophy and Cognitive Deficits Are Associated with the Formation of Oligomeric Reticulon-3 via Oxidative Stress

“…Interestingly, we found that RTN3 participates in the induction of neuronal pathology in diabetic rat brains because diabetes reduced the levels of monomeric RTN3 and increased the formation of oligomeric RTN3 (Figs. 3 and 6), which are associated with neurodegeneration and neurological dysfunction (29,30). In fact, mono-RTN3 endogenously inhibits BACE1 enzyme activity via complex formation between RTN3 and BACE1 (30,36).…”

“…3 and 6), which are associated with neurodegeneration and neurological dysfunction (29,30). In fact, mono-RTN3 endogenously inhibits BACE1 enzyme activity via complex formation between RTN3 and BACE1 (30,36). Therefore, mono-RTN3 reduction will theoretically cause an increase in BACE1 activity and A␤ generation.…”

“…Functional studies indicate that a normal increase in RTN expression substantially reduces A␤ and overexpression of RTN3 in transgenic mouse brain induces the formation of RTN3 aggregates in neurites, causing neuritic dystrophy and impairment of spatial learning and memory as well as synaptic plasticity (29). Further studies demonstrate that preformed RTN3 aggregates reduce dendritic spine density and synaptic function in transgenic mouse brains (30). Therefore, RTNs are emerging as critical factors in the pathogenesis of neurodegenerative diseases.…”

The reticulons: Guardians of the structure and function of the endoplasmic reticulum

“…2 -Correlation between some reticulon cellular functions and their potential pathological implication. association of RTN3 with BACE1 alters its trafficking itinerary to the cell surface [27].…”