Axonal generation of amyloid-β from palmitoylated APP in mitochondria-associated endoplasmic reticulum membranes
Raja Bhattacharyya,
Sophia E. Black,
Madhura S. Lotlikar,
Rebecca H. Fenn,
Mehdi Jorfi,
Dora M. Kovacs,
Rudolph E. Tanzi
Affiliations
Raja Bhattacharyya
Genetics 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 author
Sophia E. Black
Genetics 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
Madhura S. Lotlikar
Genetics 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
Rebecca H. Fenn
Genetics 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
Mehdi Jorfi
Genetics 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
Dora M. Kovacs
Genetics 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
Rudolph E. Tanzi
Genetics 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 author
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.
