Axonal generation of amyloid-β from palmitoylated APP in mitochondria-associated endoplasmic reticulum membranes
Summary: Axonal generation of Alzheimer’s disease (AD)-associated amyloid-β (Aβ) plays a key role in AD neuropathology, but the cellular mechanisms involved in its release have remained elusive. We previously reported that palmitoylated APP (palAPP) partitions to lipid rafts where it serves as a pre...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-05-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124721004733 |
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| author | Raja Bhattacharyya Sophia E. Black Madhura S. Lotlikar Rebecca H. Fenn Mehdi Jorfi Dora M. Kovacs Rudolph E. Tanzi |
| author_facet | Raja Bhattacharyya Sophia E. Black Madhura S. Lotlikar Rebecca H. Fenn Mehdi Jorfi Dora M. Kovacs Rudolph E. Tanzi |
| author_sort | Raja Bhattacharyya |
| collection | DOAJ |
| description | Summary: Axonal generation of Alzheimer’s disease (AD)-associated amyloid-β (Aβ) plays a key role in AD neuropathology, but the cellular mechanisms involved in its release have remained elusive. We previously reported that palmitoylated APP (palAPP) partitions to lipid rafts where it serves as a preferred substrate for β-secretase. Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are cholesterol-rich lipid rafts that are upregulated in AD. Here, we show that downregulating MAM assembly by either RNA silencing or pharmacological modulation of the MAM-resident sigma1 receptor (S1R) leads to attenuated β-secretase cleavage of palAPP. Upregulation of MAMs promotes trafficking of palAPP to the cell surface, β-secretase cleavage, and Aβ generation. We develop a microfluidic device and use it to show that MAM levels alter Aβ generation specifically in neuronal processes and axons, but not in cell bodies. These data suggest therapeutic strategies for reducing axonal release of Aβ and attenuating β-amyloid pathology in AD. |
| first_indexed | 2024-12-20T00:10:22Z |
| format | Article |
| id | doaj.art-fbb9f0ece7c448f19a3b11f957ce5278 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-20T00:10:22Z |
| publishDate | 2021-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-fbb9f0ece7c448f19a3b11f957ce52782022-12-21T20:00:31ZengElsevierCell Reports2211-12472021-05-01357109134Axonal generation of amyloid-β from palmitoylated APP in mitochondria-associated endoplasmic reticulum membranesRaja Bhattacharyya0Sophia E. Black1Madhura S. Lotlikar2Rebecca H. Fenn3Mehdi Jorfi4Dora M. Kovacs5Rudolph E. Tanzi6Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Henry and Allison McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Corresponding authorGenetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Henry and Allison McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USAGenetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Henry and Allison McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USAGenetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Henry and Allison McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USAGenetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Henry and Allison McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USAGenetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Henry and Allison McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USAGenetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Henry and Allison McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Corresponding authorSummary: Axonal generation of Alzheimer’s disease (AD)-associated amyloid-β (Aβ) plays a key role in AD neuropathology, but the cellular mechanisms involved in its release have remained elusive. We previously reported that palmitoylated APP (palAPP) partitions to lipid rafts where it serves as a preferred substrate for β-secretase. Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are cholesterol-rich lipid rafts that are upregulated in AD. Here, we show that downregulating MAM assembly by either RNA silencing or pharmacological modulation of the MAM-resident sigma1 receptor (S1R) leads to attenuated β-secretase cleavage of palAPP. Upregulation of MAMs promotes trafficking of palAPP to the cell surface, β-secretase cleavage, and Aβ generation. We develop a microfluidic device and use it to show that MAM levels alter Aβ generation specifically in neuronal processes and axons, but not in cell bodies. These data suggest therapeutic strategies for reducing axonal release of Aβ and attenuating β-amyloid pathology in AD.http://www.sciencedirect.com/science/article/pii/S2211124721004733Alzheimer's diseaseADAPPpalmitoylationaxonal Abetalipid rafts |
| spellingShingle | Raja Bhattacharyya Sophia E. Black Madhura S. Lotlikar Rebecca H. Fenn Mehdi Jorfi Dora M. Kovacs Rudolph E. Tanzi Axonal generation of amyloid-β from palmitoylated APP in mitochondria-associated endoplasmic reticulum membranes Cell Reports Alzheimer's disease AD APP palmitoylation axonal Abeta lipid rafts |
| title | Axonal generation of amyloid-β from palmitoylated APP in mitochondria-associated endoplasmic reticulum membranes |
| title_full | Axonal generation of amyloid-β from palmitoylated APP in mitochondria-associated endoplasmic reticulum membranes |
| title_fullStr | Axonal generation of amyloid-β from palmitoylated APP in mitochondria-associated endoplasmic reticulum membranes |
| title_full_unstemmed | Axonal generation of amyloid-β from palmitoylated APP in mitochondria-associated endoplasmic reticulum membranes |
| title_short | Axonal generation of amyloid-β from palmitoylated APP in mitochondria-associated endoplasmic reticulum membranes |
| title_sort | axonal generation of amyloid β from palmitoylated app in mitochondria associated endoplasmic reticulum membranes |
| topic | Alzheimer's disease AD APP palmitoylation axonal Abeta lipid rafts |
| url | http://www.sciencedirect.com/science/article/pii/S2211124721004733 |
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