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3 Publications visible to you, out of a total of 3
Oligodendrocytes produce amyloid-β and contribute to plaque formation alongside neurons in Alzheimer’s disease model mice

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Abstract Amyloid-β (Aβ) is thought to be neuronally derived in Alzheimer’s disease (AD). However, transcripts of amyloid precursor protein ( APP ) and amyloidogenic enzymes are equally abundant in … APP ) and amyloidogenic enzymes are equally abundant in oligodendrocytes (OLs). By cell-type-specific deletion of Bace1 in a humanized knock-in AD model, APP NLGF , we demonstrate that OLs and neurons contribute to Aβ plaque burden. For rapid plaque seeding, excitatory projection neurons must provide a threshold level of Aβ. Ultimately, our findings are relevant for AD prevention and therapeutic strategies.

Authors: Andrew Octavian Sasmita, Constanze Depp, Taisiia Nazarenko, Ting Sun, Sophie B. Siems, Erinne Cherisse Ong, Yakum B. Nkeh, Carolin Böhler, Xuan Yu, Bastian Bues, Lisa Evangelista, Shuying Mao, Barbara Morgado, Zoe Wu, Torben Ruhwedel, Swati Subramanian, Friederike Börensen, Katharina Overhoff, Lena Spieth, Stefan A. Berghoff, Katherine Rose Sadleir, Robert Vassar, Simone Eggert, Sandra Goebbels, Takashi Saito, Takaomi Saido, Gesine Saher, Wiebke Möbius, Gonçalo Castelo-Branco, Hans-Wolfgang Klafki, Oliver Wirths, Jens Wiltfang, Sarah Jäkel, Riqiang Yan, Klaus-Armin Nave

Date Published: 5th Aug 2024

Publication Type: Journal Article

Myelin insulation as a risk factor for axonal degeneration in autoimmune demyelinating disease

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Abstract Axonal degeneration determines the clinical outcome of multiple sclerosis and is thought to result from exposure of denuded axons to immune-mediated damage. Therefore, myelin is widely considered … widely considered to be a protective structure for axons in multiple sclerosis. Myelinated axons also depend on oligodendrocytes, which provide metabolic and structural support to the axonal compartment. Given that axonal pathology in multiple sclerosis is already visible at early disease stages, before overt demyelination, we reasoned that autoimmune inflammation may disrupt oligodendroglial support mechanisms and hence primarily affect axons insulated by myelin. Here, we studied axonal pathology as a function of myelination in human multiple sclerosis and mouse models of autoimmune encephalomyelitis with genetically altered myelination. We demonstrate that myelin ensheathment itself becomes detrimental for axonal survival and increases the risk of axons degenerating in an autoimmune environment. This challenges the view of myelin as a solely protective structure and suggests that axonal dependence on oligodendroglial support can become fatal when myelin is under inflammatory attack.

Authors: Erik Schäffner, Mar Bosch-Queralt, Julia M. Edgar, Maria Lehning, Judith Strauß, Niko Fleischer, Theresa Kungl, Peter Wieghofer, Stefan A. Berghoff, Tilo Reinert, Martin Krueger, Markus Morawski, Wiebke Möbius, Alonso Barrantes-Freer, Jens Stieler, Ting Sun, Gesine Saher, Markus H. Schwab, Christoph Wrede, Maximilian Frosch, Marco Prinz, Daniel S. Reich, Alexander Flügel, Christine Stadelmann, Robert Fledrich, Klaus-Armin Nave, Ruth M. Stassart

Date Published: 29th Jun 2023

Publication Type: Journal Article

Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease

Abstract (Expand)

Abstract The incidence of Alzheimer’s disease (AD), the leading cause of dementia, increases rapidly with age, but why age constitutes the main risk factor is still poorly understood. Brain ageing …s still poorly understood. Brain ageing affects oligodendrocytes and the structural integrity of myelin sheaths 1 , the latter of which is associated with secondary neuroinflammation 2,3 . As oligodendrocytes support axonal energy metabolism and neuronal health 4–7 , we hypothesized that loss of myelin integrity could be an upstream risk factor for neuronal amyloid-β (Aβ) deposition, the central neuropathological hallmark of AD. Here we identify genetic pathways of myelin dysfunction and demyelinating injuries as potent drivers of amyloid deposition in mouse models of AD. Mechanistically, myelin dysfunction causes the accumulation of the Aβ-producing machinery within axonal swellings and increases the cleavage of cortical amyloid precursor protein. Suprisingly, AD mice with dysfunctional myelin lack plaque-corralling microglia despite an overall increase in their numbers. Bulk and single-cell transcriptomics of AD mouse models with myelin defects show that there is a concomitant induction of highly similar but distinct disease-associated microglia signatures specific to myelin damage and amyloid plaques, respectively. Despite successful induction, amyloid disease-associated microglia (DAM) that usually clear amyloid plaques are apparently distracted to nearby myelin damage. Our data suggest a working model whereby age-dependent structural defects of myelin promote Aβ plaque formation directly and indirectly and are therefore an upstream AD risk factor. Improving oligodendrocyte health and myelin integrity could be a promising target to delay development and slow progression of AD.

Authors: Constanze Depp, Ting Sun, Andrew Octavian Sasmita, Lena Spieth, Stefan A. Berghoff, Taisiia Nazarenko, Katharina Overhoff, Agnes A. Steixner-Kumar, Swati Subramanian, Sahab Arinrad, Torben Ruhwedel, Wiebke Möbius, Sandra Göbbels, Gesine Saher, Hauke B. Werner, Alkmini Damkou, Silvia Zampar, Oliver Wirths, Maik Thalmann, Mikael Simons, Takashi Saito, Takaomi Saido, Dilja Krueger-Burg, Riki Kawaguchi, Michael Willem, Christian Haass, Daniel Geschwind, Hannelore Ehrenreich, Ruth Stassart, Klaus-Armin Nave

Date Published: 31st May 2023

Publication Type: Journal Article

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