Amyloid-β precursor protein: Multiple fragments, numerous transport routes and mechanisms

Abstract

This review provides insight into the intraneuronal transport of the Amyloid-β Precursor Protein (APP), the prototype of an extensively posttranslationally modified and proteolytically cleaved transmembrane protein. Uncovering the intricacies of APP transport proves to be a challenging endeavor of cell biology research, deserving increased priority, since APP is at the core of the pathogenic process in Alzheimer’s disease. After being synthesized in the endoplasmic reticulum in the neuronal soma, APP enters the intracellular transport along the secretory, endocytic, and recycling routes. Along these routes, APP undergoes cleavage into defined sets of fragments, which themselves are transported – mostly independently – to distinct sites in neurons, where they exert their functions. We review the currently known routes and mechanisms of transport of full-length APP, and of APP fragments, commenting largely on the experimental challenges posed by studying transport of extensively cleaved proteins. The review emphasizes the interrelationships between the proteolytic and posttranslational modifications, the intracellular transport, and the functions of the APP species. A goal remaining to be addressed in the future is the incorporation of the various views on APP transport into a coherent picture. In this review, the disease context is only marginally addressed; the focus is on the basic biology of APP transport in normal conditions. As shown, the studies of APP transport uncovered numerous mechanisms of transport, some of them conventional, and others, novel, awaiting exploration.

Histological assessment of β‐amyloid precursor protein immunolabelled rectal biopsies aids diagnosis of equine grass sickness

“…These data extend previous findings of increased b-APP immunoreactivity in CCG sections and increased expression of b-APP in CCG protein extracts in EGS [6]. b-Amyloid precursor protein is synthesised in the endoplasmic reticulum and transported through the Golgi apparatus, plasma membrane and axons [7]. The pattern of labelling observed in control rectal submucosal neurons (Fig 1: grade 1) is consistent with this normal cellular processing of b-APP, and is similar to that observed in other neuronal populations.…”

Amyloid Precursor Proteins Are Dynamically Trafficked and Processed during Neuronal Development

“…This congruency gives us increased confidence that we have identified authentic patterns of APP trafficking and processing in healthy neurons, a point that has been contentious in past studies (Muresan and Ladescu Muresan, 2015; Niederst et al, 2015). In addition, we obtained similar patterns of immunolabeling using multiple fixation protocols and antibodies against each domain of APPL (as indicated in Figure 1A), providing further evidence that the subcellular distributions that we reported for different cleavage fragments were not simply the result of epitope masking.…”

“…The fact that we routinely observed all of these vesicle populations undergoing anterograde and retrograde transport (both in vitro and in vivo ) argues that the dynamic distribution of these proteins can be regulated by a combination of intrinsic and extrinsic factors encountered by neurons, depending on their developmental context. Whether newly synthesized APPL must first undergo transcytosis from the plasma membrane (as suggested for APP) or can be directly packaged into secretory vesicles for transport remains to be explored (Kamal et al, 2001; Andersen et al, 2005; Haass et al, 2012; Muresan and Ladescu Muresan, 2015; Niederst et al, 2015). However, our results support the proposal that APP processing can be regulated at multiple sites to match the physiological needs and pathological stresses experienced by neurons within the brain (Kamal et al, 2001; Nikolaev et al, 2009; Szodorai et al, 2009; Niederst et al, 2015).…”

“…Although initial studies argued that axonally targeted APP must undergo retrograde transport into the somatodendritic compartment before being processed (Simons et al, 1995; Yamazaki et al, 1995; Kins et al, 2006; Back et al, 2007), more recent work using stem cell-derived neurons suggests the opposite pattern: namely, that a substantial portion of full-length APP is initially inserted into the somatodendritic compartment before being transcytosed and processed in endosomal compartments. Only subsequently are different fragments packaged into distinct vesicle populations for axonal transport (Muresan et al, 2009; Muresan and Ladescu Muresan, 2015). However, because most of these studies were conducted using neuroblastoma cell lines or relied solely on the overexpression of exogenous APP, the significance of these different sorting and processing scenarios with respect to APP-dependent functions in the nervous system remained unclear.…”

Shared Molecular Mechanisms in Alzheimer's Disease and Amyotrophic Lateral Sclerosis: Neurofilament-Dependent Transport of sAPP, FUS, TDP-43 and SOD1, with Endoplasmic Reticulum-Like Tubules

“…This novel form of transport likely relies on Rtn4-containing, ER-derived tubules penetrating into neurites, at long distance [26]. Interestingly, the Reticulon protein family, to which Rtn4 belongs, has been previously linked to both AD [27] and ALS [28].…”