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Maesako, Masato

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Maesako

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Masato

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Maesako, Masato
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    Identification of the novel activity-driven interaction between synaptotagmin 1 and presenilin 1 links calcium, synapse, and amyloid beta
    (BioMed Central, 2016) Kuzuya, Akira; Zoltowska, Katarzyna; Post, Kathryn L.; Arimon, Muriel; Li, Xuejing; Svirsky, Sarah; Maesako, Masato; Muzikansky, Alona; Gautam, Vivek; Kovacs, Dora; Hyman, Bradley; Berezovska, Oksana
    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 Ca2+-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 Ca2+-sensitive PS1 modulator that could regulate synaptic Aβ, opening avenues for novel and selective synapse targeting therapeutic strategies. Electronic supplementary material The online version of this article (doi:10.1186/s12915-016-0248-3) contains supplementary material, which is available to authorized users.
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    Pathogenic PS1 phosphorylation at Ser367
    (eLife Sciences Publications, Ltd, 2017) Maesako, Masato; Horlacher, Jana; Zoltowska, Katarzyna; Kastanenka, Ksenia; Kara, Eleanna; Svirsky, Sarah; Keller, Laura J; Li, Xuejing; Hyman, Bradley; Bacskai, Brian; Berezovska, Oksana
    The high levels of serine (S) and threonine (T) residues within the Presenilin 1 (PS1) N-terminus and in the large hydrophilic loop region suggest that the enzymatic function of PS1/γ-secretase can be modulated by its ‘phosphorylated’ and ‘dephosphorylated’ states. However, the functional outcome of PS1 phosphorylation and its significance for Alzheimer’s disease (AD) pathogenesis is poorly understood. Here, comprehensive analysis using FRET-based imaging reveals that activity-driven and Protein Kinase A-mediated PS1 phosphorylation at three domains (domain 1: T74, domain 2: S310 and S313, domain 3: S365, S366, and S367), with S367 being critical, is responsible for the PS1 pathogenic ‘closed’ conformation, and resulting increase in the Aβ42/40 ratio. Moreover, we have established novel imaging assays for monitoring PS1 conformation in vivo, and report that PS1 phosphorylation induces the pathogenic conformational shift in the living mouse brain. These phosphorylation sites represent potential new targets for AD treatment. DOI: http://dx.doi.org/10.7554/eLife.19720.001
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    Dynamic presenilin 1 and synaptotagmin 1 interaction modulates exocytosis and amyloid β production
    (BioMed Central, 2017) Zoltowska, Katarzyna Marta; Maesako, Masato; Lushnikova, Iryna; Takeda, Shuko; Keller, Laura J.; Skibo, Galina; Hyman, Bradley; Berezovska, Oksana
    Background: Alzheimer’s disease (AD)-linked protein, presenilin 1 (PS1), is present at the synapse, and the knock-out of presenilin in mice leads to synaptic dysfunction. On the other hand, synaptic activity was shown to influence PS1-dependent generation of distinct amyloid β (Aβ) species. However, the precise nature of these regulations remains unclear. The current study reveals novel role of PS1 at the synapse, and deciphers how PS1 and synaptic vesicle-associated protein, synaptotagmin 1 (Syt1) modulate each other functions in neurons via direct activity-triggered interaction. Additionally, the therapeutic potential of fostering PS1-Syt1 binding is investigated as a synapse-specific strategy for AD prevention. Methods: PS1-based cell-permeable peptide targeting PS1-Syt1 binding site was designed to inhibit PS1-Syt1 interaction in neurons. PS1 conformation, synaptic vesicle exocytosis and trafficking were assayed by fluorescence lifetime imaging microscopy (FLIM), glutamate release/synaptopHluorin assay, and fluorescence recovery after photobleaching, respectively. Syt1 level and interaction with PS1 in control and sporadic AD brains were determined by immunohistochemistry and FLIM. AAV-mediated delivery of Syt1 into mouse hippocampi was used to investigate the therapeutic potential of strengthening PS1-Syt1 binding in vivo. Statistical significance was determined using two-tailed unpaired Student’s t-test, Mann-Whitney’s U-test or two-way ANOVA followed by a Bonferroni’s post-test. Results: We demonstrate that targeted inhibition of the PS1-Syt1 binding in neurons, without changing the proteins’ expression level, triggers “pathogenic” conformational shift of PS1, and consequent increase in the Aβ42/40 ratio. Moreover, our data indicate that PS1, by binding directly to Syt1, regulates synaptic vesicle trafficking and facilitates exocytosis and neurotransmitter release. Analysis of human brain tissue revealed that not only Syt1 levels but also interactions between remaining Syt1 and PS1 are diminished in sporadic AD. On the other hand, overexpression of Syt1 in mouse hippocampi was found to potentiate PS1-Syt1 binding and promote “protective” PS1 conformation. Conclusions: The study reports novel functions of PS1 and Syt1 at the synapse, and demonstrates the importance of PS1-Syt1 binding for exocytosis and safeguarding PS1 conformation. It suggests that reduction in the Syt1 level and PS1-Syt1 interactions in AD brain may present molecular underpinning of the pathogenic PS1 conformation, increased Aβ42/40 ratio, and impaired exocytosis. Electronic supplementary material The online version of this article (doi:10.1186/s13024-017-0159-y) contains supplementary material, which is available to authorized users.