Authors: Kamogawa, Kenji | Kohara, Katsuhiko | Tabara, Yasuharu | Takita, Rie | Miki, Tetsuro | Konno, Tomoko | Hata, Saori | Suzuki, Toshiharu
Article Type: Research Article
Abstract: Alcadeins (Alcs) constitute a family of neuronal type I membrane proteins (α, β, γ) that share identical localization and function to the amyloid-β protein precursor (AβPP) in the brain. Alcs are proteolyzed in neurons through successive cleavages via secretases, resulting in non-aggregative p3-Alc, where p3 corresponds to the AβPP-fragment. We found p3-Alcα detected in human plasma reflected the pathological process of amyloid-β accumulation in Alzheimer's disease (AD) patients and therefore investigated the utility of p3-Alcα as a plasma biomarker in AD. We measured p3-Alcα plasma levels in 83 sporadic-AD, 18 mild cognitive impaired (MCI), and 24 control subjects using the …sandwich-ELISA system. Pooled samples with previously published data (171 AD and 45 controls) were also analyzed. The plasma p3-Alcα concentrations in patients with AD and MCI were significantly higher compared with control subjects (224.7 ± 40.4, 223.3 ± 53.9, and 189.1 ± 32.9 pg/ml, respectively; p = 0.0012). In AD patients, the plasma p3-Alcα concentration significantly correlated with age (r = 0.23, p = 0.037) and serum creatinine levels (r = 0.23, p = 0.0012). Even after adjusting for confounding factors of age, gender, renal function, and ApoE-ε4, high plasma p3-Alcα levels were correlated with significant AD risk, with an odds ratio 1.47 (95% confidence interval: 1.18–1.93, p = 0.0019) for every 10 pg/ml increase. Pooled analysis further confirmed these findings. Increased plasma p3-Alcα, evident in the early stages of cognitive impairment, suggests that Alc metabolites are useful plasma biomarkers of AD. Show more
Keywords: Alcadein, Alzheimer's disease, amyloid-β, blood biomarker, mild cognitive impairment
DOI: 10.3233/JAD-2012-120601
Citation: Journal of Alzheimer's Disease, vol. 31, no. 2, pp. 421-428, 2012
Authors: Waragai, Masaaki | Hata, Saori | Suzuki, Toshiharu | Ishii, Ryotaro | Fujii, Chihiro | Tokuda, Takahiko | Arai, Hiroyuki | Ohrui, Takashi | Higuchi, Susumu | Yoshida, Madoka | Igarashi, Kazuei | Moriya, Masaru | Iwai, Naomichi | Uemura, Kenichi
Article Type: Research Article
Abstract: We validated the utility of SPM8 plus DARTEL (VSRAD) combined with magnetic resonance spectroscopy (1 H MRS) as an adjunct screening technique for dementia due to Alzheimer's disease (AD). We examined the posterior cingulate gyri of 228 subjects using VSRAD and 1 H MRS in addition to conventional cerebrospinal fluid biomarkers at baseline. At the 3-year follow-up, the 228 subject were classified as follows: 93 healthy subjects, 42 MCI-non-converters (MCI-NC), 25 MCI-converters to AD (MCI-C), 44 AD, 8 dementia with Lewy bodies (DLB), 5 normal pressure hydrocephalus, and 11 patients with other neurological diseases. Our results demonstrated that subjects with …increased medial temporal atrophy (MTA) severity on VSRAD, increased Cho/Cr, MI/Cr ratio, and decreased NAA/Cr and NAA/MI ratio on 1 H MRS at baseline were at risk of dementia due to AD. Receiver operating characteristic analysis showed that severity of MTA and the NAA/MI ratio distinguished patients with AD and MCI-C from controls. Furthermore, the 118 subjects without dementia and MTA showing only a decreased NAA/MI ratio at baseline developed to MCI-C, AD, and DLB 3 years later. 1 H MRS detected biochemical abnormalities preceding brain atrophy and cognitive decline. VSRAD combined with 1 H MRS may be routinely applied to screen for MCI/AD and prodromal AD in clinical practice. Show more
Keywords: Alzheimer's disease, magnetic resonance imaging, magnetic resonance spectroscopy (1H MRS), screening, SPM8 plus DARTEL (VSRAD), surrogate marker
DOI: 10.3233/JAD-132786
Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1207-1222, 2014
Authors: Nakano, Masaki | Mitsuishi, Yachiyo | Liu, Lei | Watanabe, Naoki | Hibino, Emi | Hata, Saori | Saito, Takashi | Saido, Takaomi C. | Murayama, Shigeo | Kasuga, Kensaku | Ikeuchi, Takeshi | Suzuki, Toshiharu | Nishimura, Masaki
Article Type: Research Article
Abstract: Background: Brain amyloid-β (Aβ) peptide is released into the interstitial fluid (ISF) in a neuronal activity-dependent manner, and Aβ deposition in Alzheimer’s disease (AD) is linked to baseline neuronal activity. Although the intrinsic mechanism for Aβ generation remains to be elucidated, interleukin-like epithelial-mesenchymal transition inducer (ILEI) is a candidate for an endogenous Aβ suppressor. Objective: This study aimed to access the mechanism underlying ILEI secretion and its effect on Aβ production in the brain. Methods: ILEI and Aβ levels in the cerebral cortex were monitored using a newly developed ILEI-specific ELISA and in vivo microdialysis in mutant human Aβ precursor …protein-knockin mice. ILEI levels in autopsied brains and cerebrospinal fluid (CSF) were measured using ELISA. Results: Extracellular release of ILEI and Aβ was dependent on neuronal activation and specifically on tetanus toxin-sensitive exocytosis of synaptic vesicles. However, simultaneous monitoring of extracellular ILEI and Aβ revealed that a spontaneous fluctuation of ILEI levels appeared to inversely mirror that of Aβ levels. Selective activation and inhibition of synaptic receptors differentially altered these levels. The evoked activation of AMPA-type receptors resulted in opposing changes to ILEI and Aβ levels. Brain ILEI levels were selectively decreased in AD. CSF ILEI concentration correlated with that of Aβ and were reduced in AD and mild cognitive impairment. Conclusion: ILEI and Aβ are released from distinct subpopulations of synaptic terminals in an activity-dependent manner, and ILEI negatively regulates Aβ production in specific synapse types. CSF ILEI might represent a surrogate marker for the accumulation of brain Aβ. Show more
Keywords: Alzheimer’s disease, amyloid-β, ILEI, neurotransmitter receptor, synapse
DOI: 10.3233/JAD-201174
Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 159-174, 2021
Authors: Omori, Chiori | Kaneko, Madoka | Nakajima, Etsuko | Akatsu, Hiroyasu | Waragai, Masaaki | Maeda, Masahiro | Morishima-Kawashima, Maho | Saito, Yuhki | Nakaya, Tadashi | Taru, Hidenori | Yamamoto, Tohru | Asada, Takashi | Hata, Saori | Suzuki, Toshiharu | for the Japanese Alzheimer's Disease Neuroimaging Initiative
Article Type: Research Article
Abstract: p3-Alcα is a metabolic fragment of Alcadeinα (Alcα). Similar to the generation of the p3 fragment from amyloid-β protein precursor (AβPP) processing, Alcα is cleaved by α- and γ-secretases, leading to the secretion of p3-Alcα peptides into cerebrospinal fluid (CSF). p3-Alcα is also detected in the plasma, similar to amyloid-β (Aβ), which is a metabolic fragment of AβPP cleaved by amyloidogenic β- and γ-secretases. Because p3-Alcα is a non-aggregatable and stable peptide, unlike aggregatable Aβ and metabolically labile p3 of AβPP, the changes of p3-Alcα in quality and/or quantity in CSF and plasma are expected to be a marker for …assessing alteration of substrate cleavage by γ-secretase, such as Aβ generation from AβPP. The present study describes a sandwich enzyme-linked immunosorbent assay for quantifying levels of p3-Alcα35, the major form of the p3-Alcα species, and examines levels of p3-Alcα35 in the plasma of three independent Japanese cohorts. In two of the three cohorts, the p3-Alcα35 levels were significantly increased with a concomitant decrease in the Mini-Mental State Examination score, or in clinically diagnosed Alzheimer's disease (AD) patients, when compared with age-matched non-demented subjects. The values were significantly lower in AD subjects who were administered donepezil, when compared to AD subjects without donepezil treatment. The increase in plasma p3-Alcα35 levels may indicate an endophenotype in subjects in whom AD is due to a progressing cognitive impairment in subjects with a γ-secretase malfunction, or a disorder of the clearance of peptides. Show more
Keywords: Alzheimer's disease, alcadein, diagnosis, donepezil, γ-secretase, p3-Alc, plasma biomarker
DOI: 10.3233/JAD-131610
Citation: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 861-870, 2014
Authors: Cam, Morgane | Durieu, Emilie | Bodin, Marion | Manousopoulou, Antigoni | Koslowski, Svenja | Vasylieva, Natalia | Barnych, Bogdan | Hammock, Bruce D. | Bohl, Bettina | Koch, Philipp | Omori, Chiori | Yamamoto, Kazuo | Hata, Saori | Suzuki, Toshiharu | Karg, Frank | Gizzi, Patrick | Erakovic Haber, Vesna | Bencetic Mihaljevic, Vlatka | Tavcar, Branka | Portelius, Erik | Pannee, Josef | Blennow, Kaj | Zetterberg, Henrik | Garbis, Spiros D. | Auvray, Pierrick | Gerber, Hermeto | Fraering, Jeremy | Fraering, Patrick C. | Meijer, Laurent
Article Type: Research Article
Abstract: Generation of amyloid-β peptides (Aβs) by proteolytic cleavage of the amyloid-β protein precursor (AβPP), especially increased production of Aβ42 /Aβ43 over Aβ40 , and their aggregation as oligomers and plaques, represent a characteristic feature of Alzheimer’s disease (AD). In familial AD (FAD), altered Aβ production originates from specific mutations of AβPP or presenilins 1/2 (PS1/PS2), the catalytic subunits of γ-secretase. In sporadic AD, the origin of altered production of Aβs remains unknown. We hypothesize that the ‘human chemical exposome’ contains products able to favor the production of Aβ42 /Aβ43 over Aβ40 and shorter Aβs. To detect such products, we screened a …library of 3500 + compounds in a cell-based assay for enhanced Aβ42 /Aβ43 production. Nine pyrazole insecticides were found to induce a β- and γ-secretase-dependent, 3-10-fold increase in the production of extracellular Aβ42 in various cell lines and neurons differentiated from induced pluripotent stem cells derived from healthy and FAD patients. Immunoprecipitation/mass spectrometry analyses showed increased production of Aβs cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and shorter. Strongly supporting a direct effect on γ-secretase activity, pyrazoles shifted the cleavage pattern of another γ-secretase substrate, alcadeinα, and shifted the cleavage of AβPP by highly purified γ-secretase toward Aβ42 /Aβ43 . Focusing on fipronil, we showed that some of its metabolites, in particular the persistent fipronil sulfone, also favor the production of Aβ42 /Aβ43 in both cell-based and cell-free systems. Fipronil administered orally to mice and rats is known to be metabolized rapidly, mostly to fipronil sulfone, which stably accumulates in adipose tissue and brain. In conclusion, several widely used pyrazole insecticides enhance the production of toxic, aggregation prone Aβ42 /Aβ43 peptides, suggesting the possible existence of environmental “Alzheimerogens” which may contribute to the initiation and propagation of the amyloidogenic process in sporadic AD. Show more
Keywords: Aβ38, Aβ40, Aβ42, Aβ43, Aβ42/Aβ40 ratio, aftins, Alzheimer’s disease, alzheimerogen, amyloid-β, amyloid-β protein precursor, fipronil, γ-secretase, human chemical exposome, pesticides, phenylpyrazoles, prevention, pyrazoles, triazines
DOI: 10.3233/JAD-170875
Citation: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1663-1681, 2018
Authors: Portelius, Erik | Durieu, Emilie | Bodin, Marion | Cam, Morgane | Pannee, Josef | Leuxe, Charlotte | Mabondzo, Aloϊse | Oumata, Nassima | Galons, Hervé | Lee, Jung Yeol | Chang, Young-Tae | Stϋber, Kathrin | Koch, Philipp | Fontaine, Gaëlle | Potier, Marie-Claude | Manousopoulou, Antigoni | Garbis, Spiros D. | Covaci, Adrian | Van Dam, Debby | De Deyn, Peter | Karg, Frank | Flajolet, Marc | Omori, Chiori | Hata, Saori | Suzuki, Toshiharu | Blennow, Kaj | Zetterberg, Henrik | Meijer, Laurent
Article Type: Research Article
Abstract: Proteolytic cleavage of the amyloid-β protein precursor (AβPP) by secretases leads to extracellular release of amyloid-β (Aβ) peptides. Increased production of Aβ42 over Aβ40 and aggregation into oligomers and plaques constitute an Alzheimer’s disease (AD) hallmark. Identifying products of the ‘human chemical exposome’ (HCE) able to induce Aβ42 production may be a key to understanding some of the initiating causes of AD and to generate non-genetic, chemically-induced AD animal models. A cell model was used to screen HCE libraries for Aβ42 inducers. Out of 3500+ compounds, six triazine herbicides were found that induced a β- and γ-secretases-dependent, 2–10 fold increase …in the production of extracellular Aβ42 in various cell lines, primary neuronal cells, and neurons differentiated from human-induced pluripotent stem cells (iPSCs). Immunoprecipitation/mass spectrometry analyses show enhanced production of Aβ peptides cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and lower, a characteristic of AD. Neurons derived from iPSCs obtained from a familial AD (FAD) patient (AβPP K724N) produced more Aβ42 versus Aβ40 than neurons derived from healthy controls iPSCs (AβPP WT). Triazines enhanced Aβ42 production in both control and AD iPSCs-derived neurons. Triazines also shifted the cleavage pattern of alcadeinα, another γ-secretase substrate, suggesting a direct effect of triazines on γ-secretase activity. In conclusion, several widely used triazines enhance the production of toxic, aggregation prone Aβ42 /Aβ43 amyloids, suggesting the possible existence of environmental “Alzheimerogens” which may contribute to the initiation and propagation of the amyloidogenic process in late-onset AD. Show more
Keywords: Alzheimer’s disease, alzheimerogen, amyloid-β, amyloid-β protein precursor, Aβ42/Aβ40 ratio, herbicides, human chemical exposome, triazines
DOI: 10.3233/JAD-160310
Citation: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1593-1605, 2016