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Zoltowska, Katarzyna

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Zoltowska

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Katarzyna

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Zoltowska, Katarzyna
Author's Publications: search.filters.isAuthorOfPublication.c008ea4d-6c74-46b4-a9db-99d128980495

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    Tau protein liquid–liquid phase separation can initiate tau aggregation
    (John Wiley and Sons Inc., 2018) Wegmann, Susanne; Eftekharzadeh, Bahareh; Tepper, Katharina; Zoltowska, Katarzyna; Bennett, Rachel; Dujardin, Simon; Laskowski, Pawel R; MacKenzie, Danny; Kamath, Tarun; Commins, Caitlin; Vanderburg, Charles; Roe, Allyson D; Fan, Zhanyun; Molliex, Amandine M; Hernandez‐Vega, Amayra; Muller, Daniel; Hyman, Anthony A; Mandelkow, Eckhard; Taylor, J Paul; Hyman, Bradley
    Abstract The transition between soluble intrinsically disordered tau protein and aggregated tau in neurofibrillary tangles in Alzheimer's disease is unknown. Here, we propose that soluble tau species can undergo liquid–liquid phase separation (LLPS) under cellular conditions and that phase‐separated tau droplets can serve as an intermediate toward tau aggregate formation. We demonstrate that phosphorylated or mutant aggregation prone recombinant tau undergoes LLPS, as does high molecular weight soluble phospho‐tau isolated from human Alzheimer brain. Droplet‐like tau can also be observed in neurons and other cells. We found that tau droplets become gel‐like in minutes, and over days start to spontaneously form thioflavin‐S‐positive tau aggregates that are competent of seeding cellular tau aggregation. Since analogous LLPS observations have been made for FUS, hnRNPA1, and TDP43, which aggregate in the context of amyotrophic lateral sclerosis, we suggest that LLPS represents a biophysical process with a role in multiple different neurodegenerative diseases.
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    Soluble Gamma-secretase Modulators Attenuate Alzheimer's β-amyloid Pathology and Induce Conformational Changes in Presenilin 1
    (Elsevier, 2017) Raven, Frank; Ward, Joseph F.; Zoltowska, Katarzyna; Wan, Yu; Bylykbashi, Enjana; Miller, Sean J.; Shen, Xunuo; Choi, Se Hoon; Rynearson, Kevin D.; Berezovska, Oksana; Wagner, Steven L.; Tanzi, Rudolph; Zhang, Can
    A central pathogenic event of Alzheimer's disease (AD) is the accumulation of the Aβ42 peptide, which is generated from amyloid-β precursor protein (APP) via cleavages by β- and γ-secretase. We have developed a class of soluble 2-aminothiazole γ-secretase modulators (SGSMs) that preferentially decreases Aβ42 levels. However, the effects of SGSMs in AD animals and cells expressing familial AD mutations, as well as the mechanism of γ-secretase modulation remain largely unknown. Here, a representative of this SGSM scaffold, SGSM-36, was investigated using animals and cells expressing FAD mutations. SGSM-36 preferentially reduced Aβ42 levels without affecting either α- and β-secretase processing of APP nor Notch processing. Furthermore, an allosteric site was identified within the γ-secretase complex that allowed access of SGSM-36 using cell-based, fluorescence lifetime imaging microscopy analysis. Collectively, these studies provide mechanistic insights regarding SGSMs of this class and reinforce their therapeutic potential in AD.
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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