Axonal amyloid precursor protein and its fragments undergo somatodendritic endocytosis and processing
| Autor: | Emily D. Niederst, Sol M. Reyna, Lawrence S.B. Goldstein |
|---|---|
| Přispěvatelé: | Forscher, Paul |
| Rok vydání: | 2015 |
| Předmět: |
Aging
Cellular differentiation Neurodegenerative Inbred C57BL Alzheimer's Disease Medical and Health Sciences Mice Amyloid beta-Protein Precursor Amyloid precursor protein 2.1 Biological and endogenous factors Aetiology Cells Cultured Mice Knockout Benzodiazepinones Microscopy Microscopy Confocal Cultured biology Cell Differentiation Articles Microfluidic Analytical Techniques Biological Sciences Endocytosis Cell biology Biochemistry Cell Biology of Disease Confocal Neurological Signal transduction Oligopeptides Signal Transduction Cells Knockout 1.1 Normal biological development and functioning Cell Line Underpinning research mental disorders Acquired Cognitive Impairment Animals Humans Secretion Molecular Biology Embryonic Stem Cells Amyloid beta-Peptides Hydrazones Neurosciences Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Cell Biology Dendrites Embryonic stem cell Axons Peptide Fragments Brain Disorders Mice Inbred C57BL Somatodendritic compartment Luminescent Proteins nervous system biology.protein Dementia Amyloid Precursor Protein Secretases Amyloid precursor protein secretase Developmental Biology |
| Zdroj: | Molecular biology of the cell, vol 26, iss 2 Molecular Biology of the Cell |
| Popis: | In mouse and human neurons, axonally secreted amyloid precursor protein (APP) fragments are processed in the cell body before being sorted into the axon in a process that requires endocytosis for the processing, but not axonal delivery, of APP. Deposition of potentially neurotoxic Aβ fragments derived from amyloid precursor protein (APP) at synapses may be a key contributor to Alzheimer's disease. However, the location(s) of proteolytic processing and subsequent secretion of APP fragments from highly compartmentalized, euploid neurons that express APP and processing enzymes at normal levels is not well understood. To probe the behavior of endogenous APP, particularly in human neurons, we developed a system using neurons differentiated from human embryonic stem cells, cultured in microfluidic devices, to enable direct biochemical measurements from axons. Using human or mouse neurons in these devices, we measured levels of Aβ, sAPPα, and sAPPβ secreted solely from axons. We found that a majority of the fragments secreted from axons were processed in the soma, and many were dependent on somatic endocytosis for axonal secretion. We also observed that APP and the β-site APP cleaving enzyme were, for the most part, not dependent on endocytosis for axonal entry. These data establish that axonal entry and secretion of APP and its proteolytic processing products traverse different pathways in the somatodendritic compartment before axonal entry. |
| Databáze: | OpenAIRE |
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