RTN/Nogo in forming Alzheimer's neuritic plaques

Abstract

One of the pathological hallmarks in brains of patients with Alzheimer's disease (AD) is the presence of neuritic plaques, in which amyloid deposits are surrounded by reactive gliosis and dystrophic neurites. Within neuritic plaques, reticulon 3 (RTN3), a homolog of Nogo protein, appears to regulate the formation of both amyloid deposition via negative modulation of BACE1 activity and dystrophic neurites via the formation of RTN3 aggregates. Transgenic mice over-expressing RTN3, but not the other known markers of dystrophic neurites in AD brain, spontaneously develop RTN3-immunoreactive dystrophic neurites. The presence of dystrophic neurites impairs cognition. Blocking abnormal RTN3 aggregation will increase the available RTN3 monomer and is therefore a promising therapeutic strategy for enhancing cognitive function in AD patients.

Figure 1. Interaction of RTN3 with BACE1 on the membrane

RTN3 adopts a ω-shape membrane topology. The C-terminal region specified in red block mediates the interaction between BACE1 and RTN3. The sequence with two transmembrane domains affects the folding of RTN3 and is consequently important for proper interaction to occur. Increased expression of RTN3 will not only cause reduced levels of BACE1 on the cell surface, but will also create a spatial hindrance between BACE1 and its APP substrate. Both can result in reduction of sAPPβ, CTF99 and Aβ.

Figure 2. RIDNs are abundantly present in brains of AD cases

Postmortem brain sections were stained with antibody R458 for RTN3 (green), ubiquitin (red) or AT8 for phosphorylated tau (red). Under the staining conditions, both ubiquitin and AT8 antibodies recognized neurofibrillary tangles and dystrophic neurites. However, RTN3 immunoreactive dystrophic neurites were obviously more abundant in the hippocampal region of AD cases. (The merged figures were previously published in Hu et al. (Hu et al., 2007))

Figure 3. Hypothetical formation of RIDNs

RTN3 is normally localized along the axon and in the growth cone. Its transport in the axon is expected to be bidirectional. When the levels of RTN3 are high, RTN3 is more transported in the anterograde direction but perhaps not in the retrograde direction. This imbalance causes an accumulation of RTN3 in the axonal region, which may form aggregates and cause axonal swelling. Transport of nutrients and other essential materials along the axon may therefore be impaired, eventually causing axonal degeneration. These altered or swollen axonal termini containing either RTN3 (green) alone or a combination of RTN3 and other dystrophic neurite marker proteins such as APP and ubiquitin (red) are a component of neuritic plaques and may lead to deficits in synaptic transmission and plasticity. Such deficits manifest as cognitive impairment in disease states.