APP and APLP2 interact with the synaptic release machinery and facilitate transmitter release at hippocampal synapses
The amyloid precursor protein (APP), whose mutations cause familial Alzheimer’s disease, interacts with the synaptic release machinery, suggesting a role in neurotransmission. Here we mapped this interaction to the NH2-terminal region of the APP intracellular domain. A peptide encompassing this bind...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2015-11-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/09743 |
| _version_ | 1811227400389787648 |
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| author | Tomas Fanutza Dolores Del Prete Michael J Ford Pablo E Castillo Luciano D’Adamio |
| author_facet | Tomas Fanutza Dolores Del Prete Michael J Ford Pablo E Castillo Luciano D’Adamio |
| author_sort | Tomas Fanutza |
| collection | DOAJ |
| description | The amyloid precursor protein (APP), whose mutations cause familial Alzheimer’s disease, interacts with the synaptic release machinery, suggesting a role in neurotransmission. Here we mapped this interaction to the NH2-terminal region of the APP intracellular domain. A peptide encompassing this binding domain -named JCasp- is naturally produced by a γ-secretase/caspase double-cut of APP. JCasp interferes with the APP-presynaptic proteins interaction and, if linked to a cell-penetrating peptide, reduces glutamate release in acute hippocampal slices from wild-type but not APP deficient mice, indicating that JCasp inhibits APP function.The APP-like protein-2 (APLP2) also binds the synaptic release machinery. Deletion of APP and APLP2 produces synaptic deficits similar to those caused by JCasp. Our data support the notion that APP and APLP2 facilitate transmitter release, likely through the interaction with the neurotransmitter release machinery. Given the link of APP to Alzheimer’s disease, alterations of this synaptic role of APP could contribute to dementia. |
| first_indexed | 2024-04-12T09:41:54Z |
| format | Article |
| id | doaj.art-1a1b7ceca1044600ba25eaf041a2231d |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T09:41:54Z |
| publishDate | 2015-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-1a1b7ceca1044600ba25eaf041a2231d2022-12-22T03:38:03ZengeLife Sciences Publications LtdeLife2050-084X2015-11-01410.7554/eLife.09743APP and APLP2 interact with the synaptic release machinery and facilitate transmitter release at hippocampal synapsesTomas Fanutza0Dolores Del Prete1Michael J Ford2Pablo E Castillo3Luciano D’Adamio4Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, United StatesDepartment of Microbiology and Immunology, Albert Einstein College of Medicine, New York, United StatesMS Bioworks, LLC, Ann Arbor, United StatesDominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, United StatesDepartment of Microbiology and Immunology, Albert Einstein College of Medicine, New York, United StatesThe amyloid precursor protein (APP), whose mutations cause familial Alzheimer’s disease, interacts with the synaptic release machinery, suggesting a role in neurotransmission. Here we mapped this interaction to the NH2-terminal region of the APP intracellular domain. A peptide encompassing this binding domain -named JCasp- is naturally produced by a γ-secretase/caspase double-cut of APP. JCasp interferes with the APP-presynaptic proteins interaction and, if linked to a cell-penetrating peptide, reduces glutamate release in acute hippocampal slices from wild-type but not APP deficient mice, indicating that JCasp inhibits APP function.The APP-like protein-2 (APLP2) also binds the synaptic release machinery. Deletion of APP and APLP2 produces synaptic deficits similar to those caused by JCasp. Our data support the notion that APP and APLP2 facilitate transmitter release, likely through the interaction with the neurotransmitter release machinery. Given the link of APP to Alzheimer’s disease, alterations of this synaptic role of APP could contribute to dementia.https://elifesciences.org/articles/09743neurodegenerationsynaptic transmissionAmyloid precursor proteinsynaptic vesicleDementia |
| spellingShingle | Tomas Fanutza Dolores Del Prete Michael J Ford Pablo E Castillo Luciano D’Adamio APP and APLP2 interact with the synaptic release machinery and facilitate transmitter release at hippocampal synapses eLife neurodegeneration synaptic transmission Amyloid precursor protein synaptic vesicle Dementia |
| title | APP and APLP2 interact with the synaptic release machinery and facilitate transmitter release at hippocampal synapses |
| title_full | APP and APLP2 interact with the synaptic release machinery and facilitate transmitter release at hippocampal synapses |
| title_fullStr | APP and APLP2 interact with the synaptic release machinery and facilitate transmitter release at hippocampal synapses |
| title_full_unstemmed | APP and APLP2 interact with the synaptic release machinery and facilitate transmitter release at hippocampal synapses |
| title_short | APP and APLP2 interact with the synaptic release machinery and facilitate transmitter release at hippocampal synapses |
| title_sort | app and aplp2 interact with the synaptic release machinery and facilitate transmitter release at hippocampal synapses |
| topic | neurodegeneration synaptic transmission Amyloid precursor protein synaptic vesicle Dementia |
| url | https://elifesciences.org/articles/09743 |
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