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Article ; Online: Mechanisms of amyloid-β34 generation indicate a pivotal role for BACE1 in amyloid homeostasis

Irem Ulku / Filip Liebsch / S. Can Akerman / Jana F. Schulz / Luka Kulic / Christoph Hock / Claus Pietrzik / Alessandro Di Spiezio / Gopal Thinakaran / Paul Saftig / Gerhard Multhaup

Scientific Reports, Vol 13, Iss 1, Pp 1-

2023 Volume 15

Abstract: Abstract The beta‑site amyloid precursor protein (APP) cleaving enzyme (BACE1) was discovered due to its “amyloidogenic” activity which contributes to the production of amyloid-beta (Aβ) peptides. However, BACE1 also possesses an “amyloidolytic” activity, ...

Abstract	Abstract The beta‑site amyloid precursor protein (APP) cleaving enzyme (BACE1) was discovered due to its “amyloidogenic” activity which contributes to the production of amyloid-beta (Aβ) peptides. However, BACE1 also possesses an “amyloidolytic” activity, whereby it degrades longer Aβ peptides into a non‑toxic Aβ34 intermediate. Here, we examine conditions that shift the equilibrium between BACE1 amyloidogenic and amyloidolytic activities by altering BACE1/APP ratios. In Alzheimer disease brain tissue, we found an association between elevated levels of BACE1 and Aβ34. In mice, the deletion of one BACE1 gene copy reduced BACE1 amyloidolytic activity by ~ 50%. In cells, a stepwise increase of BACE1 but not APP expression promoted amyloidolytic cleavage resulting in dose-dependently increased Aβ34 levels. At the cellular level, a mislocalization of surplus BACE1 caused a reduction in Aβ34 levels. To align the role of γ-secretase in this pathway, we silenced Presenilin (PS) expression and identified PS2-γ-secretase as the main γ-secretase that generates Aβ40 and Aβ42 peptides serving as substrates for BACE1’s amyloidolytic cleavage to generate Aβ34.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2023-02-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A human antibody against pathologic IAPP aggregates protects beta cells in type 2 diabetes models

Fabian Wirth / Fabrice D. Heitz / Christine Seeger / Ioana Combaluzier / Karin Breu / Heather C. Denroche / Julien Thevenet / Melania Osto / Paolo Arosio / Julie Kerr-Conte / C. Bruce Verchere / François Pattou / Thomas A. Lutz / Marc Y. Donath / Christoph Hock / Roger M. Nitsch / Jan Grimm

Nature Communications, Vol 14, Iss 1, Pp 1-

2023 Volume 15

Abstract: Abstract In patients with type 2 diabetes, pancreatic beta cells progressively degenerate and gradually lose their ability to produce insulin and regulate blood glucose. Beta cell dysfunction and loss is associated with an accumulation of aggregated ... ...

Abstract	Abstract In patients with type 2 diabetes, pancreatic beta cells progressively degenerate and gradually lose their ability to produce insulin and regulate blood glucose. Beta cell dysfunction and loss is associated with an accumulation of aggregated forms of islet amyloid polypeptide (IAPP) consisting of soluble prefibrillar IAPP oligomers as well as insoluble IAPP fibrils in pancreatic islets. Here, we describe a human monoclonal antibody selectively targeting IAPP oligomers and neutralizing IAPP aggregate toxicity by preventing membrane disruption and apoptosis in vitro. Antibody treatment in male rats and mice transgenic for human IAPP, and human islet-engrafted mouse models of type 2 diabetes triggers clearance of IAPP oligomers resulting in beta cell protection and improved glucose control. These results provide new evidence for the pathological role of IAPP oligomers and suggest that antibody-mediated removal of IAPP oligomers could be a pharmaceutical strategy to support beta cell function in type 2 diabetes.
Keywords	Science ; Q
Subject code	571
Language	English
Publishing date	2023-10-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A human antibody selective for transthyretin amyloid removes cardiac amyloid through phagocytic immune cells

Aubin Michalon / Andreas Hagenbuch / Christian Huy / Evita Varela / Benoit Combaluzier / Thibaud Damy / Ole B. Suhr / Maria J. Saraiva / Christoph Hock / Roger M. Nitsch / Jan Grimm

Nature Communications, Vol 12, Iss 1, Pp 1-

2021 Volume 12

Abstract: Analyzing memory B cell repertoires of the healthy elderly enabled Michalon et al. to develop a recombinant human antibody selective for transthyretin amyloid. This antibody removes cardiac amyloid through recruitment of phagocytic immune cells. ...

Abstract	Analyzing memory B cell repertoires of the healthy elderly enabled Michalon et al. to develop a recombinant human antibody selective for transthyretin amyloid. This antibody removes cardiac amyloid through recruitment of phagocytic immune cells.
Keywords	Science ; Q
Language	English
Publishing date	2021-05-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Physical activity is associated with lower cerebral beta-amyloid and cognitive function benefits from lifetime experience-a study in exceptional aging.

Valerie Treyer / Rafael S Meyer / Andreas Buchmann / Giovanni A G Crameri / Sandro Studer / Antje Saake / Esmeralda Gruber / Paul G Unschuld / Roger M Nitsch / Christoph Hock / Anton F Gietl

PLoS ONE, Vol 16, Iss 2, p e

2021 Volume 0247225

Abstract: Background Exceptional agers (85+ years) are characterized by preserved cognition presumably due to high cognitive reserve. In the current study, we examined whether personality, risk and protective factors for dementia as well as quality of life are ... ...

Abstract	Background Exceptional agers (85+ years) are characterized by preserved cognition presumably due to high cognitive reserve. In the current study, we examined whether personality, risk and protective factors for dementia as well as quality of life are associated with core features of Alzheimer's disease (amyloid-deposition and hippocampal volume) as well as cognition in exceptional aging. Methods We studied 49 exceptional agers (average 87.8 years, range 84-94 years), with preserved activities of daily living and absence of dementia. All participants received a detailed clinical and neuropsychological examination. We used established questionnaires to measure lifetime experience, personality, recent physical and cognitive activity as well as quality of life. Cerebral amyloid-deposition was estimated by 18-[F]-Flutemetamol-PET and manual hippocampal volumetry was performed on 3D T1 MRI images. Results In this sample of exceptional agers with preserved activities of daily living, we found intact cognitive performance in the subjects with the highest amyloid-load in the brain, but a lower quality of life with respect to autonomy as well as higher neuroticism. Higher self-reported physical activity in the last twelve months went with a lower amyloid load. Higher self-reported leisure-time/ not work-related activity went with better executive functioning at older age. Conclusion Even in exceptional aging, high amyloid load may subtly influence personality and quality of life. Our findings support a close relationship between high physical activity and low amyloid-deposition and underscore the importance of extracurricular activities for executive functions. As executive functions are known to be a central resource for everyday functioning in fostering extracurricular activities may be effective in delaying the onset of dementia.
Keywords	Medicine ; R ; Science ; Q
Subject code	150
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Oxidative stress and altered mitochondrial protein expression in the absence of amyloid-β and tau pathology in iPSC-derived neurons from sporadic Alzheimer's disease patients

Julian H. Birnbaum / Debora Wanner / Anton F. Gietl / Antje Saake / Thomas M. Kündig / Christoph Hock / Roger M. Nitsch / Christian Tackenberg

Stem Cell Research, Vol 27, Iss , Pp 121-

2018 Volume 130

Abstract: Mitochondrial dysfunction is a prominent feature of Alzheimer's disease (AD) and increased production of reactive oxygen species (ROS) has been described in postmortem brain samples and animal models. However, these observations were made at a late stage ...

Abstract	Mitochondrial dysfunction is a prominent feature of Alzheimer's disease (AD) and increased production of reactive oxygen species (ROS) has been described in postmortem brain samples and animal models. However, these observations were made at a late stage of disease and the inability to examine an early, presymptomatic phase in human neurons impeded our understanding of cause or consequence of mitochondrial dysfunction in AD. We used human induced pluripotent stem cell-derived neuronal cells (iN cells) from sporadic AD (SAD) patients and healthy control subjects (HCS) to show aberrant mitochondrial function in patient-derived cells. We observed that neuronal cultures from some patients produced more ROS and displayed higher levels of DNA damage. Furthermore, patient-derived cells showed increased levels of oxidative phosphorylation chain complexes, whereas mitochondrial fission and fusion proteins were not affected. Surprisingly, these effects neither correlated with Aβ nor phosphorylated and total tau levels. Synaptic protein levels were also unaffected in SAD iN cells. The results of this study give new insights into constitutional metabolic changes in neurons from subjects prone to develop Alzheimer's pathology. They suggest that increased ROS production may have an integral role in the development of sporadic AD prior to the appearance of amyloid and tau pathology. Keywords: Alzheimer's disease, Induced pluripotent stem cells, Induced neuronal cells, Sporadic AD, Mitochondria, Aβ
Keywords	Biology (General) ; QH301-705.5
Subject code	571
Language	English
Publishing date	2018-03-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Brain areas with normatively greater cerebral perfusion in early life may be more susceptible to beta amyloid deposition in late life

Irene B. Meier / Patrick J. Lao / Anton Gietl / Robert S. Vorburger / José Gutierrez / Christopher M. Holland / Charles R.G. Guttmann / Dominik S. Meier / Alfred Buck / Roger M. Nitsch / Christoph Hock / Paul G. Unschuld / Adam M. Brickman

Cerebral Circulation, Cognition and Behavior, Vol 1, Iss , Pp 100001- (2020)

2020

Abstract: Background: The amyloid cascade hypothesis characterizes the stereotyped progression of pathological changes in Alzheimer's disease (AD) beginning with beta amyloid deposition, but does not address the reasons for amyloid deposition. Brain areas with ... ...

Abstract	Background: The amyloid cascade hypothesis characterizes the stereotyped progression of pathological changes in Alzheimer's disease (AD) beginning with beta amyloid deposition, but does not address the reasons for amyloid deposition. Brain areas with relatively higher neuronal activity, metabolic demand, and production of reactive oxygen species in earlier life may have higher beta amyloid deposition in later life. The aim of this study was to investigate early life patterns of perfusion and late life patterns of amyloid deposition to determine the extent to which normative cerebral perfusion predisposes specific regions to future beta amyloid deposition. Materials and Methods: One hundred twenty-eight healthy, older human subjects (age: 56–87 years old; 44% women) underwent positron emission tomography (PET) imaging with [11C]PiB for measures of amyloid burden. Cerebral perfusion maps derived from 47 healthy younger adults (age: 22–49; 47%) who had undergone single photon emission computed tomography (SPECT) imaging, were averaged to create a normative template, representative of young, healthy adults. Perfusion and amyloid measures were investigated in 31 cortical regions from the Hammers atlas. We examined the spatial relationship between normative perfusion patterns and amyloid pathophysiology. Results: The pattern of increasing perfusion (temporal lobe<parietal lobe<frontal lobe<insula/cingulate gyrus<occipital lobe; F(4,26)=7.8, p = 0.0003) in young, healthy adults was not exactly identical to but approximated the pattern of increasing amyloid burden (temporal lobe<occipital lobe<frontal lobe<parietal lobe<insula/cingulate gyrus; F(4,26)=5.0, p = 0.004) in older adults. However, investigating subregions within cortical lobes provided consistent agreement between ranked normative perfusion patterns and expected Thal staging of amyloid progression in AD (Spearman r = 0.39, p = 0.03). Conclusion: Our findings suggest that brain areas with normatively greater perfusion may be more ...<br />
Keywords	Cerebral perfusion ; amyloid ; Alzheimer's disease ; Specialties of internal medicine ; RC581-951 ; Neurosciences. Biological psychiatry. Neuropsychiatry ; RC321-571
Subject code	610
Language	English
Publishing date	2020-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Aβ34 is a BACE1-derived degradation intermediate associated with amyloid clearance and Alzheimer’s disease progression

Filip Liebsch / Luka Kulic / Charlotte Teunissen / Adeola Shobo / Irem Ulku / Vivienne Engelschalt / Mark A. Hancock / Wiesje M. van der Flier / Peter Kunach / Pedro Rosa-Neto / Philip Scheltens / Judes Poirier / Paul Saftig / Randall J. Bateman / John Breitner / Christoph Hock / Gerhard Multhaup

Nature Communications, Vol 10, Iss 1, Pp 1-

2019 Volume 15

Abstract: Aβ34 is generated from degradation of Aβ40 and Aβ42 by β-secretase. Here, the authors show that Aβ34 is a marker for amyloid clearance and is elevated in the CSF of patients that go on to convert from mild cognitive impairment to Alzheimer’s disease, ... ...

Abstract	Aβ34 is generated from degradation of Aβ40 and Aβ42 by β-secretase. Here, the authors show that Aβ34 is a marker for amyloid clearance and is elevated in the CSF of patients that go on to convert from mild cognitive impairment to Alzheimer’s disease, suggesting it may be a useful biomarker.
Keywords	Science ; Q
Language	English
Publishing date	2019-05-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Aβ34 is a BACE1-derived degradation intermediate associated with amyloid clearance and Alzheimer’s disease progression

Nature Communications, Vol 10, Iss 1, Pp 1-

2019 Volume 15

Abstract	Aβ34 is generated from degradation of Aβ40 and Aβ42 by β-secretase. Here, the authors show that Aβ34 is a marker for amyloid clearance and is elevated in the CSF of patients that go on to convert from mild cognitive impairment to Alzheimer’s disease, suggesting it may be a useful biomarker.
Keywords	Science ; Q
Language	English
Publishing date	2019-05-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Visualization and quantification of APP intracellular domain-mediated nuclear signaling by bimolecular fluorescence complementation.

Florian Riese / Sonja Grinschgl / Manuel T Gersbacher / Natalie Russi / Christoph Hock / Roger M Nitsch / Uwe Konietzko

PLoS ONE, Vol 8, Iss 9, p e

2013 Volume 76094

Abstract: Background The amyloid precursor protein (APP) intracellular domain (AICD) is released from full-length APP upon sequential cleavage by either α- or β-secretase followed by γ-secretase. Together with the adaptor protein Fe65 and the histone ... ...

Abstract	Background The amyloid precursor protein (APP) intracellular domain (AICD) is released from full-length APP upon sequential cleavage by either α- or β-secretase followed by γ-secretase. Together with the adaptor protein Fe65 and the histone acetyltransferase Tip60, AICD forms nuclear multiprotein complexes (AFT complexes) that function in transcriptional regulation. Objective To develop a medium-throughput machine-based assay for visualization and quantification of AFT complex formation in cultured cells. Methods We used cotransfection of bimolecular fluorescence complementation (BiFC) fusion constructs of APP and Tip60 for analysis of subcellular localization by confocal microscopy and quantification by flow cytometry (FC). Results Our novel BiFC-constructs show a nuclear localization of AFT complexes that is identical to conventional fluorescence-tagged constructs. Production of the BiFC signal is dependent on the adaptor protein Fe65 resulting in fluorescence complementation only after Fe65-mediated nuclear translocation of AICD and interaction with Tip60. We applied the AFT-BiFC system to show that the Swedish APP familial Alzheimer's disease mutation increases AFT complex formation, consistent with the notion that AICD mediated nuclear signaling mainly occurs following APP processing through the amyloidogenic β-secretase pathway. Next, we studied the impact of posttranslational modifications of AICD on AFT complex formation. Mutation of tyrosine 682 in the YENPTY motif of AICD to phenylalanine prevents phosphorylation resulting in increased nuclear AFT-BiFC signals. This is consistent with the negative impact of tyrosine phosphorylation on Fe65 binding to AICD. Finally, we studied the effect of oxidative stress. Our data shows that oxidative stress, at a level that also causes cell death, leads to a reduction in AFT-BiFC signals. Conclusion We established a new method for visualization and FC quantification of the interaction between AICD, Fe65 and Tip60 in the nucleus based on BiFC. It enables flow ...
Keywords	Medicine ; R ; Science ; Q
Subject code	571
Language	English
Publishing date	2013-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Levels and determinants of inflammatory biomarkers in a Swiss population-based sample (CoLaus study).

Pedro Marques-Vidal / Murielle Bochud / François Bastardot / Thomas Lüscher / François Ferrero / Jean-Michel Gaspoz / Fred Paccaud / Adrian Urwyler / Roland von Känel / Christoph Hock / Gérard Waeber / Martin Preisig / Peter Vollenweider

PLoS ONE, Vol 6, Iss 6, p e

2011 Volume 21002

Abstract: OBJECTIVE: to assess the levels and determinants of interleukin (IL)-1β, IL-6, tumour necrosis factor (TNF)-α and C-reactive protein (CRP) in a healthy Caucasian population. METHODS: population sample of 2884 men and 3201 women aged 35 to 75. IL-1β, IL-6 ...

Abstract	OBJECTIVE: to assess the levels and determinants of interleukin (IL)-1β, IL-6, tumour necrosis factor (TNF)-α and C-reactive protein (CRP) in a healthy Caucasian population. METHODS: population sample of 2884 men and 3201 women aged 35 to 75. IL-1β, IL-6 and TNF-α were assessed by a multiplexed particle-based flow cytometric assay and CRP by an immunometric assay. RESULTS: Spearman rank correlations between duplicate cytokine measurements (N = 80) ranged between 0.89 and 0.96; intra-class correlation coefficients ranged between 0.94 and 0.97, indicating good reproducibility. Among the 6085 participants, 2289 (37.6%), 451 (7.4%) and 43 (0.7%) had IL-1β, IL-6 and TNF-α levels below detection limits, respectively. Median (interquartile range) for participants with detectable values were 1.17 (0.48-3.90) pg/ml for IL-1β; 1.47 (0.71-3.53) pg/ml for IL-6; 2.89 (1.82-4.53) pg/ml for TNF-α and 1.3 (0.6-2.7) ng/ml for CRP. On multivariate analysis, greater age was the only factor inversely associated with IL-1β levels. Male sex, increased BMI and smoking were associated with greater IL-6 levels, while no relationship was found for age and leisure-time PA. Male sex, greater age, increased BMI and current smoking were associated with greater TNF-α levels, while no relationship was found with leisure-time PA. CRP levels were positively related to age, BMI and smoking, and inversely to male sex and physical activity. CONCLUSION: Population-based levels of several cytokines were established. Increased age and BMI, and to a lesser degree sex and smoking, significantly and differentially impact cytokine levels, while leisure-time physical activity has little effect.
Keywords	Medicine ; R ; Science ; Q
Subject code	333
Language	English
Publishing date	2011-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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