title: Identification of the novel activity-driven interaction between synaptotagmin 1 and presenilin 1 links calcium, synapse, and amyloid beta.
abstract: BACKGROUND
  Synaptic loss strongly correlates with memory deterioration. Local accumulation of amyloid β (Aβ) peptide, and neurotoxic Aβ42 in particular, due to abnormal neuronal activity may underlie synaptic dysfunction, neurodegeneration, and memory impairments. To gain an insight into molecular events underlying neuronal activity-regulated Aβ production at the synapse, we explored functional outcomes of the newly discovered calcium-dependent interaction between Alzheimer's disease-associated presenilin 1 (PS1)/γ-secretase and synaptic vesicle proteins.
  
  
  RESULTS
  Mass spectrometry screen of mouse brain lysates identified synaptotagmin 1 (Syt1) as a novel synapse-specific PS1-binding partner that shows Ca(2+)-dependent PS1 binding profiles in vitro and in vivo. We found that Aβ level, and more critically, conformation of the PS1 and the Aβ42/40 ratio, are affected by Syt1 overexpression or knockdown, indicating that Syt1 and its interaction with PS1 might regulate Aβ production at the synapse. Moreover, β-secretase 1 (BACE1) stability, β- and γ-secretase activity, as well as intracellular compartmentalization of PS1 and BACE1, but not of amyloid precursor protein (APP), nicastrin (Nct), presenilin enhancer 2 (Pen-2), or synaptophysin (Syp) were altered in the absence of Syt1, suggesting a selective effect of Syt1 on PS1 and BACE1 trafficking.
  
  
  CONCLUSIONS
  Our findings identify Syt1 as a novel Ca(2+)-sensitive PS1 modulator that could regulate synaptic Aβ, opening avenues for novel and selective synapse targeting therapeutic strategies.
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.
authors.forename: Akira
authors.initials: A
authors.lastname: Kuzuya
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.
authors.forename: Katarzyna M
authors.initials: KM
authors.lastname: Zoltowska
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Post
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.
authors.forename: Muriel
authors.initials: M
authors.lastname: Arimon
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.
authors.forename: Xuejing
authors.initials: X
authors.lastname: Li
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Svirsky
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.
authors.forename: Masato
authors.initials: M
authors.lastname: Maesako
authors.affiliation: MGH Biostatistics Center, Massachusetts General Hospital, Boston, MA, 02114, USA.
authors.forename: Alona
authors.initials: A
authors.lastname: Muzikansky
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Gautam
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.
authors.forename: Dora
authors.initials: D
authors.lastname: Kovacs
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA. oberezovska@mgh.harvard.edu.
authors.forename: Oksana
authors.initials: O
authors.lastname: Berezovska
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000032:analysis / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D053764:Presenilin-1 / Q000032:analysis / Q000378:metabolism*; D060066:Protein Interaction Maps; D051381:Rats; D013569:Synapses / Q000378:metabolism / Q000473:pathology; D050863:Synaptotagmin I / Q000032:analysis / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D053764:Presenilin-1; D050863:Synaptotagmin I; D053829:Amyloid Precursor Protein Secretases; D002118:Calcium
keywords: Alzheimer’s disease; Beta amyloid; Presenilin 1; Synaptotagmin 1