Identification of the novel activity-driven interaction between synaptotagmin 1 and presenilin 1 links calcium, synapse, and amyloid beta

Kuzuya, Akira; Zoltowska, Katarzyna Marta; Post, Kathryn; Arimon, Muriel; Li, Xuejing; Svirsky, Sarah; Maesako, Masato; Muzikansky, Alona; Gautam, Vivek; Kovacs, Dora M.; Hyman, Bradley T.; Berezovska, Oksana

doi:10.1186/s12915-016-0248-3

Cited by 33 publications

(67 citation statements)

References 59 publications

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“…An increase in the intracellular calcium levels and the shift of PS1 toward the pathogenic state were recorded in KCl-treated neurons (Figures 5A, B). Importantly our previous data demonstrating an increase in the Aβ42/40 ratio upon the rise in intracellular calcium (20) support the functional relevance of the observed shift within the PS1 subdomain organization.…”

Section: Increased Intracellular Calcium Load Due To High Aa42/40 Ratsupporting

confidence: 51%

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Interrelationship between Changes in the Amyloid β 42/40 Ratio and Presenilin 1 Conformation

Zoltowska

Maesako

Berezovska

2016

Mol Med

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The ratio of the longer (Aβ42/Aβ43) to shorter (Aβ40) species is a critical factor determining amyloid fibril formation, neurotoxicity and progression of the amyloid pathology in Alzheimer's disease. The relative levels of the different Aβ species are affected by activity and conformation of the γ-secretase complex catalytic component presenilin 1 (PS1). The enzyme exists in a dynamic equilibrium of the conformational states, with so-called "close" conformation associated with the shift of the γ-secretase cleavage toward the production of longer, neurotoxic Aβ species. In the current study, fluorescence lifetime imaging microscopy, spectral Förster resonance energy transfer, calcium imaging and cytotoxicity assays were utilized to explore a reciprocal link between the Aβ42 and Aβ40 peptides present at various ratios and PS1 conformation in primary neurons. We report that exposure to Aβ peptides at a relatively high ratio of Aβ42/40 causes conformational change within the PS1 subdomain architecture toward the pathogenic "closed" state. Mechanistically, the Aβ42/40 peptides present at the relatively high ratio increase intracellular calcium levels, which were shown to trigger pathogenic PS1 conformation. This indicates that there is a reciprocal cross-talk between the extracellular Aβ peptides and PS1 conformation within a neuron, with Aβ40 showing some protective effect. The pathogenic shift within the PS1 domain architecture may further shift the production of Aβ peptides toward the longer, neurotoxic Aβ species. These findings link elevated calcium, Aβ42 and PS1/γ-secretase conformation, and offer possible mechanistic explanation of the impending exacerbation of the amyloid pathology.

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Section: Increased Intracellular Calcium Load Due To High Aa42/40 Ratsupporting

confidence: 51%

“…Spectral FRET assay was performed as described previously (20). Briefly, the GFP was excited using the Argon laser…”

Section: Spectral Fretmentioning

confidence: 99%

Interrelationship between Changes in the Amyloid β 42/40 Ratio and Presenilin 1 Conformation

Zoltowska

Maesako

Berezovska

2016

Mol Med

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“…Cells were sorted by a cell sorter to obtain homogenous cultures of APP mGFP -expressing or APP mGFP + APP mCherry -expressing cells. The cells were fixed and the FLIM analysis was performed as described previously [45]. Briefly, pulsing Chameleon Ti:Sapphire laser (Coherent Inc., Santa Clara, CA) was used to excite GFP donor fluorophore (two-photon excitation at 780 nm wavelength).…”

Section: Methodsmentioning

confidence: 99%

Palmitoylated APP Forms Dimers, Cleaved by BACE1

et al. 2016

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A major rate-limiting step for Aβ generation and deposition in Alzheimer’s disease brains is BACE1-mediated cleavage (β-cleavage) of the amyloid precursor protein (APP). We previously reported that APP undergoes palmitoylation at two cysteine residues (Cys186 and Cys187) in the E1-ectodomain. 8–10% of total APP is palmitoylated in vitro and in vivo. Palmitoylated APP (palAPP) shows greater preference for β-cleavage than total APP in detergent resistant lipid rafts. Protein palmitoylation is known to promote protein dimerization. Since dimerization of APP at its E1-ectodomain results in elevated BACE1-mediated cleavage of APP, we have now investigated whether palmitoylation of APP affects its dimerization and whether this leads to elevated β-cleavage of the protein. Here we report that over 90% of palAPP is dimerized while only ~20% of total APP forms dimers. PalAPP-dimers are predominantly cis-oriented while total APP dimerizes in both cis- and trans-orientation. PalAPP forms dimers 4.5-times more efficiently than total APP. Overexpression of the palmitoylating enzymes DHHC7 and DHHC21 that increase palAPP levels and Aβ release, also increased APP dimerization in cells. Conversely, inhibition of APP palmitoylation by pharmacological inhibitors reduced APP-dimerization in coimmunoprecipitation and FLIM/FRET assays. Finally, in vitro BACE1-activity assays demonstrate that palmitoylation-dependent dimerization of APP promotes β-cleavage of APP in lipid-rich detergent resistant cell membranes (DRMs), when compared to total APP. Most importantly, generation of sAPPβ-sAPPβ dimers is dependent on APP-palmitoylation while total sAPPβ generation is not. Since BACE1 shows preference for palAPP dimers over total APP, palAPP dimers may serve as novel targets for effective β-cleavage inhibitors of APP as opposed to BACE1 inhibitors.

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“…9 for APP). Both proteins are abundantly expressed in the presynaptic active zone 10–12 where they interact with proteins of the synaptic release machinery 13–15 . Therefore, the physiological role of both PS and APP in presynaptic mechanisms through interactions with proteins of the presynaptic release machinery needs to be investigated.…”

Section: Introductionmentioning

confidence: 99%

Presenilin-mediated cleavage of APP regulates synaptotagmin-7 and presynaptic plasticity

Barthet

Jordà-Siquier

Ruli-Masante

et al. 2018

Preprint

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SUMMARYPresenilin (PS), the catalytic subunit of γ-secretase and its main substrate the amyloid precursor protein (APP) are mutated in a large majority of patients with familial Alzheimer disease. PS and APP interact with proteins of the neurotransmitter release machinery but the functional consequences of these interactions are unknown. Here we report that genetic deletion of presynaptic PS markedly decreases the axonal expression of the Ca2+ sensor synaptotagmin-7 (Syt7), and impairs synaptic facilitation and replenishment of release-competent synaptic vesicles. These properties are fully restored by presynaptic re-expression of Syt7. The regulation of Syt7 expression occurs post-transcriptionally and depends on γ-secretase activity. In the combined absence of both APP and PS1, the loss of Syt7 is prevented, indicating that the action of γ-secretase on presynaptic mechanisms depends on its substrate APP. The molecular mechanism involves the substrate of PS, APP-βCterminal (APP-βCTF), which interacts with Syt7 and accumulates in synaptic terminals under conditions of pharmacological or genetic inhibition of γ-secretase. These results reveal a role of PS in presynaptic mechanisms through regulation of Syt7 by APP-dependent cleavage, and highlight aberrant synaptic vesicle processing as a possible new pathway 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

Cited by 33 publications

References 59 publications

Interrelationship between Changes in the Amyloid β 42/40 Ratio and Presenilin 1 Conformation

Interrelationship between Changes in the Amyloid β 42/40 Ratio and Presenilin 1 Conformation

Palmitoylated APP Forms Dimers, Cleaved by BACE1

Presenilin-mediated cleavage of APP regulates synaptotagmin-7 and presynaptic plasticity

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