Axonal transport of APP and the spatial regulation of APP cleavage and function in neuronal cells
Open accessAbstract
Over two decades have passed since the original discovery of amyloid precursor protein (APP). While physiological function(s) of APP still remain a matter of debate, consensus exists that the proteolytic processing of this protein represents a critical event in the life of neurons and that abnormalities in this process are instrumental in Alzheimer's disease (AD) pathogenesis. Specific molecular components involved in APP proteolysis have been identified, and their enzymatic activities characterized in great detail. As specific proteolytic fragments of APP are identified and novel physiological effects for these fragments are revealed, more obvious becomes our need to understand the spatial organization of APP proteolysis. Valuable insights on this process have been obtained through the study of non-neuronal cells. However, much less is known about the topology of APP processing in neuronal cells, which are characterized by their remarkably complex cellular architecture and extreme degree of polarization. In this review, we discuss published literature addressing various molecular mechanisms and components involved in the trafficking and subcellular distribution of APP and APP secretases in neurons. These include the relevant machinery involved in their sorting, the identity of membranous organelles in which APP is transported, and the molecular motor-based mechanisms involved in their translocation. We also review experimental evidence specifically addressing the processing of APP at the axonal compartment. Understanding neuron-specific mechanisms of APP processing would help illuminating the physiological roles of APP-derived proteolytic fragments and provide novel insights on AD pathogenesis.
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Movement of vesicles and endo-lysosomal compartments along axons is a key part of amyloid fibril formation and vesicle-mediated aggregation of Tau proteins.
“The movement of vesicles and endo-lysosomal compartments along axons is a key part of amyloid fibril formation and vesicle-mediated aggregation of Tau proteins [7, 87].”
From Abnormal accumulation of extracellular vesicles in hippocampal dystrophic axons and regulation by the primary cilia in Alzheimer's disease (2023) · cites this paper as [7]
The 'Axonal transport of APP' section describes movement of membrane-bounded organelles along axons, and 'Functional roles of APP metabolites in neurons' links axonally transported APP to Aβ deposited in amyloid plaques. The paper does not establish that this movement is a key part of amyloid fibril formation or vesicle-mediated Tau aggregation; it also does not identify the transported compartments specifically as endo-lysosomal. (LLM, conf=0.84)
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- Authors
- Brunholz, S., Sisodia, S., Lorenzo, A., Deyts, C., Kins, S., & Morfini, G.
- Affiliations
- University of Kaiserslautern (DE)
- University of Chicago (US)
- Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
- University of Illinois Chicago (US)
- Corresponding author
- Morfini, Gerardo
- Venue
- Experimental Brain Research
- Published
- 2011-09-30
- Volume
- 217
- Issue
- 3-4
- Pages
- 353-364
- ISSN
- 0014-4819 (ISSN-L)
- 1432-1106
- PMC
- PMC3670699
- OpenAlex
- W1989258392
- Cited by
- 92
- References
- 116
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 2 · 2023: 6 · 2022: 5 · 2021: 6 · 2020: 7 · 2019: 8 · 2018: 4 · 2017: 8 · 2016: 9 · 2015: 6 · 2014: 9 · 2013: 7 · 2012: 8
- FWCI
- 0.86
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Experimental Brain Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Brain Research Foundation
- Eisai
- National Institutes of Health
- National Institute on Aging (R01AG021494)
- National Institute of Neurological Disorders and Stroke (R01NS066942, R01 NS066942A)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- amyloid precursor protein, axonal transport, APP proteolysis, Alzheimer's disease, neuronal polarity, intracellular trafficking, motor proteins, axons, neurons
- MeSH terms
- Alzheimer Disease, Animals, Axonal Transport, Humans, Neurons, Protein Processing, Post-Translational, Subcellular Fractions, Amyloid beta-Protein Precursor, Protein Transport, Proteolysis
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