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Article ; Online: Curcumin tautomerization in the mechanism of pentameric amyloid- β42 oligomers disassembly

Matsui, Atsuya / Bellier, Jean-Pierre / Hayashi, Daiki / Ishibe, Takafumi / Nakamura, Yoshiaki / Taguchi, Hiroyasu / Naruse, Nobuyasu / Mera, Yutaka

Biochemical and Biophysical Research Communications. 2023 July, v. 666 p.68-75

2023

Abstract: Alzheimer's disease is a neurologic disorder characterized by the accumulation of extracellular deposits of amyloid-β (Aβ) fibrils in the brain of patients. The key etiologic agent in Alzheimer's disease is not known; however oligomeric Aβ appears ... ...

Abstract	Alzheimer's disease is a neurologic disorder characterized by the accumulation of extracellular deposits of amyloid-β (Aβ) fibrils in the brain of patients. The key etiologic agent in Alzheimer's disease is not known; however oligomeric Aβ appears detrimental to neuronal functions and increases Aβ fibrils deposition. Previous research has shown that curcumin, a phenolic pigment of turmeric, has an effect on Aβ assemblies, although the mechanism remains unclear. In this study, we demonstrate that curcumin disassembles pentameric oligomers made from synthetic Aβ42 peptides (pentameric oAβ42), using atomic force microscopy imaging followed by Gaussian analysis. Since curcumin shows keto-enol structural isomerism (tautomerism), the effect of keto-enol tautomerism on its disassembly was investigated. We have found that curcumin derivatives capable of keto-enol tautomerization also disassemble pentameric oAβ42, while, a curcumin derivative incapable of tautomerization did not affect the integrity of pentameric oAβ42. These experimental findings indicate that keto-enol tautomerism plays an essential role in the disassembly. We propose a mechanism for oAβ42 disassembly by curcumin based on molecular dynamics calculations of the tautomerism. When curcumin and its derivatives bind to the hydrophobic regions of oAβ42, the keto-form changes predominantly to the enol-form; this transition is associated with structural (twisting, planarization and rigidification) and potential energy changes that give curcumin enough force to act as a torsion molecular-spring that eventually disassembles pentameric oAβ42. This proposed mechanism sheds new light on keto-enol tautomerism as a relevant chemical feature for designing such novel therapeutic drugs that target protein aggregation.
Keywords	Alzheimer disease ; atomic force microscopy ; brain ; constitutional isomerization ; curcumin ; etiological agents ; hydrophobicity ; molecular dynamics ; neurons ; peptides ; potential energy ; research ; tautomerization ; therapeutics ; turmeric ; Amyloid-β ; Oligomers ; Tautomerism
Language	English
Dates of publication	2023-07
Size	p. 68-75.
Publishing place	Elsevier Inc.
Document type	Article ; Online
Note	Use and reproduction
ZDB-ID	205723-2
ISSN	0006-291X ; 0006-291X
ISSN (online)	0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2023.04.076
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Article: Editorial: Brain Evolution: Clues From Aquatic Organisms.

de Girolamo, Paolo / Bellier, Jean-Pierre / D'Angelo, Livia

Frontiers in neuroanatomy

2021 Volume 15, Page(s) 683489

Language	English
Publishing date	2021-05-07
Publishing country	Switzerland
Document type	Editorial
ZDB-ID	2452969-2
ISSN	1662-5129
ISSN	1662-5129
DOI	10.3389/fnana.2021.683489
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Article ; Online: Optimization of 3D Immunofluorescence Analysis and Visualization Using IMARIS and MeshLab.

Abu Bakar, Zulzikry Hafiz / Bellier, Jean-Pierre / Wan Ngah, Wan Zurinah / Yanagisawa, Daijiro / Mukaisho, Ken-Ichi / Tooyama, Ikuo

Cells

2023 Volume 12, Issue 2

Abstract: The precision of colocalization analysis is enhanced by 3D and is potentially more accurate than 2D. Even though 3D improves the visualization of colocalization analysis, rendering a colocalization model may generate a model with numerous polygons. We ... ...

Abstract	The precision of colocalization analysis is enhanced by 3D and is potentially more accurate than 2D. Even though 3D improves the visualization of colocalization analysis, rendering a colocalization model may generate a model with numerous polygons. We developed a 3D colocalization model of FtMt/LC3 followed by simplification. Double immunofluorescence staining of FtMt and LC3 was conducted, and stacked images were acquired. We used IMARIS to render the 3D colocalization model of FtMt/LC3 and further processed it with MeshLab to decimate and generate a less complex colocalization model. We examined the available simplification algorithm using MeshLab in detail and evaluated the feasibility of each procedure in generating a model with less complexity. The quality of the simplified model was subsequently assessed. MeshLab's available shaders were scrutinized to facilitate the spatial colocalization determination. Finally, we showed that QECD was the most effective method for reducing the polygonal complexity of the colocalization model without compromising its quality. In addition, we would recommend implementing the x-ray shader, which we found useful for visualizing colocalization. As 3D was found to be more accurate in quantifying colocalization, our study provides a novel and dependable method for rendering 3D models for colocalization analysis.
MeSH term(s)	Imaging, Three-Dimensional/methods ; X-Rays ; Fluorescent Antibody Technique
Language	English
Publishing date	2023-01-04
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells12020218
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Article: New insight on the enteric cholinergic innervation of the pig colon by central and peripheral nervous systems: reduction by repeated loperamide administration.

Yuan, Pu-Qing / Li, Tao / Million, Mulugeta / Larauche, Muriel / Atmani, Karim / Bellier, Jean-Pierre / Taché, Yvette

Frontiers in neuroscience

2023 Volume 17, Page(s) 1204233

Abstract: Introduction: The central and peripheral nervous systems provide cholinergic innervation in the colon. The ability to assess their neuroanatomical distinctions is still a challenge. The pig is regarded as a relevant translational model due to the close ... ...

Abstract	Introduction: The central and peripheral nervous systems provide cholinergic innervation in the colon. The ability to assess their neuroanatomical distinctions is still a challenge. The pig is regarded as a relevant translational model due to the close similarity of its enteric nervous system (ENS) with that of human. Opioid-induced constipation is one of the most common side effects of opioid therapy. Methods: We developed an approach to differentiate the central and peripheral cholinergic innervation of the pig colon using double immunolabeling with a novel mouse anti-human peripheral type of choline acetyltransferase (hpChAT) antibody combined with a rabbit anti-common type of ChAT (cChAT) antibody, a reliable marker of cholinergic neurons in the central nervous system. We examined their spatial configurations in 3D images of the ENS generated from CLARITY-cleared colonic segments. The density was quantitated computationally using Imaris 9.7. We assessed changes in the distal colon induced by daily oral treatment for 4 weeks with the μ opioid receptor agonist, loperamide (0.4 or 3 mg/kg). Results: The double labeling showed strong cChAT immunoreactive (ir) fibers in the cervical vagus nerve and neuronal somata and fibers in the ventral horn of the sacral (S2) cord while hpChAT immunoreactivity was visualized only in the ENS but not in the vagus or sacral neural structures indicating the selectivity of these two antibodies. In the colonic myenteric plexus, dense hpChAT-ir neurons and fibers and varicose cChAT-ir fibers surrounding hpChAT-ir neurons were simultaneously visualized in 3D. The density of cChAT-ir varicose fibers in the outer submucosal plexus of both males and females were higher in the transverse and distal colon than in the proximal colon and in the myenteric plexus compared to the outer submucosal plexus and there was no cChAT innervation in the inner submucosal plexus. The density of hpChAT in the ENS showed no segmental or plexus differences in both sexes. Loperamide at the highest dose significantly decreased the density hpChAT-ir fibers + somata in the myenteric plexus of the distal colon. Discussion: These data showed the distinct density of central cholinergic innervation between myenteric and submucosal plexuses among colonic segments and the localization of cChAT-ir fibers around peripheral hpChAT neurons in 3D. The reduction of cholinergic myenteric innervation by chronic opiate treatment points to target altered prokinetic cholinergic pathway to counteract opiate constipation.
Language	English
Publishing date	2023-08-15
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-4548
ISSN (online)	1662-453X
ISSN	1662-4548
DOI	10.3389/fnins.2023.1204233
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Article ; Online: Curcumin tautomerization in the mechanism of pentameric amyloid- β42 oligomers disassembly.

Matsui, Atsuya / Bellier, Jean-Pierre / Hayashi, Daiki / Ishibe, Takafumi / Nakamura, Yoshiaki / Taguchi, Hiroyasu / Naruse, Nobuyasu / Mera, Yutaka

Biochemical and biophysical research communications

2023 Volume 666, Page(s) 68–75

Abstract	Alzheimer's disease is a neurologic disorder characterized by the accumulation of extracellular deposits of amyloid-β (Aβ) fibrils in the brain of patients. The key etiologic agent in Alzheimer's disease is not known; however oligomeric Aβ appears detrimental to neuronal functions and increases Aβ fibrils deposition. Previous research has shown that curcumin, a phenolic pigment of turmeric, has an effect on Aβ assemblies, although the mechanism remains unclear. In this study, we demonstrate that curcumin disassembles pentameric oligomers made from synthetic Aβ42 peptides (pentameric oAβ42), using atomic force microscopy imaging followed by Gaussian analysis. Since curcumin shows keto-enol structural isomerism (tautomerism), the effect of keto-enol tautomerism on its disassembly was investigated. We have found that curcumin derivatives capable of keto-enol tautomerization also disassemble pentameric oAβ42, while, a curcumin derivative incapable of tautomerization did not affect the integrity of pentameric oAβ42. These experimental findings indicate that keto-enol tautomerism plays an essential role in the disassembly. We propose a mechanism for oAβ42 disassembly by curcumin based on molecular dynamics calculations of the tautomerism. When curcumin and its derivatives bind to the hydrophobic regions of oAβ42, the keto-form changes predominantly to the enol-form; this transition is associated with structural (twisting, planarization and rigidification) and potential energy changes that give curcumin enough force to act as a torsion molecular-spring that eventually disassembles pentameric oAβ42. This proposed mechanism sheds new light on keto-enol tautomerism as a relevant chemical feature for designing such novel therapeutic drugs that target protein aggregation.
MeSH term(s)	Humans ; Curcumin/chemistry ; Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; Brain/metabolism ; Amyloid/metabolism ; Peptide Fragments/metabolism
Chemical Substances	Curcumin (IT942ZTH98) ; Amyloid beta-Peptides ; Amyloid ; Peptide Fragments
Language	English
Publishing date	2023-05-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	205723-2
ISSN	1090-2104 ; 0006-291X ; 0006-291X
ISSN (online)	1090-2104 ; 0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2023.04.076
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Article ; Online: LC3/FtMt Colocalization Patterns Reveal the Progression of FtMt Accumulation in Nigral Neurons of Patients with Progressive Supranuclear Palsy.

Abu Bakar, Zulzikry Hafiz / Bellier, Jean-Pierre / Yanagisawa, Daijiro / Kato, Tomoko / Mukaisho, Ken-Ichi / Tooyama, Ikuo

International journal of molecular sciences

2022 Volume 23, Issue 1

Abstract: Mitochondrial ferritin (FtMt) is a mitochondrial iron storage protein associated with neurodegenerative diseases. In patients with progressive supranuclear palsy (PSP), FtMt was shown to accumulate in nigral neurons. Here, we investigated FtMt and LC3 in ...

Abstract	Mitochondrial ferritin (FtMt) is a mitochondrial iron storage protein associated with neurodegenerative diseases. In patients with progressive supranuclear palsy (PSP), FtMt was shown to accumulate in nigral neurons. Here, we investigated FtMt and LC3 in the post-mortem midbrain of PSP patients to reveal novel aspects of the pathology. Immunohistochemistry was used to assess the distribution and abnormal changes in FtMt and LC3 immunoreactivities. Colocalization analysis using double immunofluorescence was performed, and subcellular patterns were examined using 3D imaging and modeling. In the substantia nigra pars compacta (SNc), strong FtMt-IR and LC3-IR were observed in the neurons of PSP patients. In other midbrain regions, such as the superior colliculus, the FtMt-IR and LC3-IR remained unchanged. In the SNc, nigral neurons were categorized into four patterns based on subcellular LC3/FtMt immunofluorescence intensities, degree of colocalization, and subcellular overlapping. This categorization suggested that concomitant accumulation of LC3/FtMt is related to mitophagy processes. Using the LC3-IR to stage neuronal damage, we retraced LC3/FtMt patterns and revealed the progression of FtMt accumulation in nigral neurons. Informed by these findings, we proposed a hypothesis to explain the function of FtMt during PSP progression.
MeSH term(s)	Biomarkers ; Disease Susceptibility ; Ferritins/genetics ; Ferritins/metabolism ; Fluorescent Antibody Technique ; Humans ; Immunohistochemistry ; Mesencephalon/metabolism ; Mesencephalon/pathology ; Microtubule-Associated Proteins/genetics ; Microtubule-Associated Proteins/metabolism ; Mitochondria/metabolism ; Mitochondrial Proteins/genetics ; Mitochondrial Proteins/metabolism ; Mitophagy ; Neurons/metabolism ; Protein Binding ; Protein Transport ; Substantia Nigra/metabolism ; Substantia Nigra/pathology ; Supranuclear Palsy, Progressive/diagnosis ; Supranuclear Palsy, Progressive/etiology ; Supranuclear Palsy, Progressive/metabolism
Chemical Substances	Biomarkers ; MAP1LC3A protein, human ; Microtubule-Associated Proteins ; Mitochondrial Proteins ; mitochondrial ferritin, human ; Ferritins (9007-73-2)
Language	English
Publishing date	2022-01-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23010537
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Article ; Online: Structure Optimization of the Toxic Conformation Model of Amyloid β42 by Intramolecular Disulfide Bond Formation.

Matsushima, Yuka / Irie, Yumi / Kageyama, Yusuke / Bellier, Jean-Pierre / Tooyama, Ikuo / Maki, Takahito / Kume, Toshiaki / Yanagita, Ryo C / Irie, Kazuhiro

Chembiochem : a European journal of chemical biology

2022 Volume 23, Issue 8, Page(s) e202200029

Abstract: Amyloid β (Aβ) oligomers play a critical role in the pathology of Alzheimer's disease. Recently, we reported that a conformation-restricted Aβ42 with an intramolecular disulfide bond through cysteine residues at positions 17/28 formed stable oligomers ... ...

Abstract	Amyloid β (Aβ) oligomers play a critical role in the pathology of Alzheimer's disease. Recently, we reported that a conformation-restricted Aβ42 with an intramolecular disulfide bond through cysteine residues at positions 17/28 formed stable oligomers with potent cytotoxicity. To further optimize this compound as a toxic conformer model, we synthesized three analogues with a combination of cysteine and homocysteine at positions 17/28. The analogues with Cys-Cys, Cys-homoCys, or homoCys-Cys, but not the homoCys-homoCys analogue, exhibited potent cytotoxicity against SH-SY5Y and THP-1 cells even at 10 nM. In contrast, the cytotoxicity of conformation-restricted analogues at positions 16/29 or 18/27 was significantly weaker than that of wild-type Aβ42. Furthermore, thioflavin-T assay, non-denaturing gel electrophoresis, and morphological studies suggested that the majority of these conformation-restricted analogues exists in an oligomeric state in cell culture medium, indicating that the toxic conformation of Aβ42, rather than the oligomeric state, is essential to induce cytotoxicity.
MeSH term(s)	Alzheimer Disease/pathology ; Amyloid/chemistry ; Amyloid beta-Peptides/chemistry ; Amyloid beta-Peptides/toxicity ; Cysteine ; Disulfides/chemistry ; Humans ; Peptide Fragments/chemistry ; Peptide Fragments/toxicity
Chemical Substances	Amyloid ; Amyloid beta-Peptides ; Disulfides ; Peptide Fragments ; amyloid beta-protein (1-42) ; Cysteine (K848JZ4886)
Language	English
Publishing date	2022-03-03
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2020469-3
ISSN	1439-7633 ; 1439-4227
ISSN (online)	1439-7633
ISSN	1439-4227
DOI	10.1002/cbic.202200029
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Article: Identification of Fibrinogen as a Plasma Protein Binding Partner for Lecanemab Biosimilar IgG: Implications for Alzheimer's Disease Therapy.

Bellier, Jean-Pierre / Román Viera, Andrea M / Christiano, Caitlyn / Anzai, Juliana A U / Moreno, Stephanie / Campbell, Emily C / Godwin, Lucas / Li, Amy / Chen, Alan Y / Alam, Sarah / Saba, Adrianna / Yoo, Han Bin / Yang, Hyun-Sik / Chhatwal, Jasmeer P / Selkoe, Dennis J / Liu, Lei

bioRxiv : the preprint server for biology

2024

Abstract: Objective: Recombinant monoclonal therapeutic antibodies like lecanemab, which target amyloid beta in Alzheimer's disease, offer a promising approach for modifying the disease progression. Due to its relatively short half-life, Lecanemab, administered ... ...

Abstract	Objective: Recombinant monoclonal therapeutic antibodies like lecanemab, which target amyloid beta in Alzheimer's disease, offer a promising approach for modifying the disease progression. Due to its relatively short half-life, Lecanemab, administered as a bi-monthly infusion (typically 10mg/kg) has a relatively brief half-life. Interaction with abundant plasma proteins binder in the bloodstream can affect pharmacokinetics of drugs, including their half-life. In this study we investigated potential plasma protein binding interaction to lecanemab using lecanemab biosimilar. Methods: Lecanemab biosimilar used in this study was based on publicly available sequences. ELISA and Western blotting were used to assess lecanemab biosimilar immunoreactivity in the fractions human plasma sample obtained through size exclusion chromatography. The binding of lecanemab biosimilar to candidate binders was confirmed by Western blotting, ELISA, and surface plasmon resonance analysis. Results: Using a combination of equilibrium dialysis, ELISA, and Western blotting in human plasma, we first describe the presence of likely plasma protein binding partner to lecanemab biosimilar, and then identify fibrinogen as one of them. Utilizing surface plasmon resonance, we confirmed that lecanemab biosimilar does bind to fibrinogen, although with lower affinity than to monomeric amyloid beta. Interpretation: In the context of lecanemab therapy, these results imply that fibrinogen levels could impact the levels of free antibodies in the bloodstream and that fibrinogen might serve as a reservoir for lecanemab. More broadly, these results indicate that plasma protein binding may be an important consideration when clinically utilizing therapeutic antibodies in neurodegenerative disease.
Language	English
Publishing date	2024-05-01
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.05.01.591892
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Article ; Online: Intrinsic cholinergic innervation in the human sigmoid colon revealed using CLARITY, three-dimensional (3D) imaging, and a novel anti-human peripheral choline acetyltransferase (hpChAT) antiserum.

Yuan, Pu-Qing / Bellier, Jean-Pierre / Li, Tao / Kwaan, Mary R / Kimura, Hiroshi / Taché, Yvette

Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society

2020 Volume 33, Issue 4, Page(s) e14030

Abstract: Background: We previously reported the specificity of a novel anti-human peripheral choline acetyltransferase (hpChAT) antiserum for immunostaining of cholinergic neuronal cell bodies and fibers in the human colon. In this study, we investigate 3D ... ...

Abstract	Background: We previously reported the specificity of a novel anti-human peripheral choline acetyltransferase (hpChAT) antiserum for immunostaining of cholinergic neuronal cell bodies and fibers in the human colon. In this study, we investigate 3D architecture of intrinsic cholinergic innervation in the human sigmoid colon and the relationship with nitrergic neurons in the enteric plexus. Methods: We developed a modified CLARITY tissue technique applicable for clearing human sigmoid colon specimens and immunostaining with hpChAT antiserum and co-labeling with neuronal nitric oxide synthase (nNOS) antibody. The Z-stack confocal images were processed for 3D reconstruction/segmentation/digital tracing and computational quantitation by Imaris 9.2 and 9.5. Key results: In the mucosa, a local micro-neuronal network formed of hpChAT-ir fibers and a few neuronal cell bodies were digitally assembled. Three layers of submucosal plexuses were displayed in 3D structure that were interconnected by hpChAT-ir fiber bundles and hpChAT-ir neurons were rarely co-labeled by nNOS. In the myenteric plexus, 30.1% of hpChAT-ir somas including Dogiel type I and II were co-labeled by nNOS and 3 classes of hpChAT-ir nerve fiber strands were visualized in 3D images and videos. The density and intensity values of hpChAT-ir fibers in 3D structure were significantly higher in the circular than in the longitudinal layer. Conclusions and inferences: The intrinsic cholinergic innervation in the human sigmoid colon was demonstrated layer by layer for the first time in 3D microstructures. This may open a new venue to assess the structure-function relationships and pathological alterations in colonic diseases.
MeSH term(s)	Adult ; Choline O-Acetyltransferase/analysis ; Choline O-Acetyltransferase/metabolism ; Cholinergic Neurons/chemistry ; Cholinergic Neurons/metabolism ; Colon, Sigmoid/chemistry ; Colon, Sigmoid/diagnostic imaging ; Colon, Sigmoid/metabolism ; Enteric Nervous System/chemistry ; Enteric Nervous System/diagnostic imaging ; Enteric Nervous System/metabolism ; Female ; Humans ; Imaging, Three-Dimensional/methods ; Immunohistochemistry/methods ; Male ; Middle Aged
Chemical Substances	Choline O-Acetyltransferase (EC 2.3.1.6)
Language	English
Publishing date	2020-11-10
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1186328-6
ISSN	1365-2982 ; 1350-1925
ISSN (online)	1365-2982
ISSN	1350-1925
DOI	10.1111/nmo.14030
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Article ; Online: Uncovering elevated tau TPP motif phosphorylation in the brain of Alzheimer's disease patients.

Bellier, Jean-Pierre / Cai, Yuqi / Alam, Sarah M / Wiederhold, Thorsten / Aiello, Arica / Vogelgsang, Jonathan S / Berretta, Sabina / Chhatwal, Jasmeer P / Selkoe, Dennis J / Liu, Lei

Alzheimer's & dementia : the journal of the Alzheimer's Association

2023 Volume 20, Issue 3, Page(s) 1573–1585

Abstract: Introduction: A wide array of post-translational modifications of the tau protein occurs in Alzheimer's disease (AD) and they are critical to pathogenesis and biomarker development. Several promising tau markers, pT181, pT217, and pT231, rely on ... ...

Abstract	Introduction: A wide array of post-translational modifications of the tau protein occurs in Alzheimer's disease (AD) and they are critical to pathogenesis and biomarker development. Several promising tau markers, pT181, pT217, and pT231, rely on increased phosphorylation within a common molecular motif threonine-proline-proline (TPP). Methods: We validated new and existing antibodies against pT217, pT231, pT175, and pT181, then combined immunohistochemistry (IHC) and immunoassays (ELISA) to broadly examine the phosphorylation of the tau TPP motif in AD brains. Results: The tau burden, as examined by IHC and ELISA, correlates to Braak stages across all TPP sites. Moreover, we observed regional variability across four TPP motif phosphorylation sites in multiple brains of sporadic AD patients. Discussion: We conclude that there is an elevation of TPP tau phosphorylation in AD brains as disease advances. The regional variability of pTPP tau suggests that examining different phosphorylation sites is essential for a comprehensive assessment of tau pathology.
MeSH term(s)	Humans ; Alzheimer Disease/pathology ; tau Proteins/metabolism ; Phosphorylation ; Threonine/metabolism ; Brain/pathology ; Proline/metabolism
Chemical Substances	tau Proteins ; Threonine (2ZD004190S) ; Proline (9DLQ4CIU6V)
Language	English
Publishing date	2023-12-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	2211627-8
ISSN	1552-5279 ; 1552-5260
ISSN (online)	1552-5279
ISSN	1552-5260
DOI	10.1002/alz.13557
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