Universität zu Köln

Yamoah, Alfred, Tripathi, Priyanka, Sechi, Antonio, Koehler, Christoph, Guo, Haihong, Chandrasekar, Akila, Nolte, Kay Wilhelm, Wruck, Christoph Jan, Katona, Istvan, Anink, Jasper, Troost, Dirk, Aronica, Eleonora, Steinbusch, Harry, Weis, Joachim and Goswami, Anand (2020). Aggregates of RNA Binding Proteins and ER Chaperones Linked to Exosomes in Granulovacuolar Degeneration of the Alzheimer's Disease Brain. J. Alzheimers Dis., 75 (1). S. 139 - 157. AMSTERDAM: IOS PRESS. ISSN 1875-8908

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Abstract

Granulovacuolar degeneration (GVD) occurs in Alzheimer's disease (AD) brain due to compromised autophagy. Endoplasmic reticulum (ER) function and RNA binding protein (RBP) homeostasis regulate autophagy. We observed that the ER chaperones Glucose - regulated protein, 78 KDa (GRP78/BiP), Sigma receptor 1 (SigR1), and Vesicle-associated membrane protein associated protein B (VAPB) were elevated in many AD patients' subicular neurons. However, those neurons which were affected by GVD showed lower chaperone levels, and there was only minor co-localization of chaperones with GVD bodies (GVBs), suggesting that neurons lacking sufficient chaperone-mediated proteo stasis enter the GVD pathway. Consistent with this notion, granular, incipient pTau aggregates in human AD and pR5 tau transgenic mouse neurons were regularly co-localized with increased chaperone immunoreactivity, whereas neurons with mature neurofibrillary tangles lacked both the chaperone buildup and significant GVD. On the other hand, APP/PS1 (APPswe/PSEN1dE9) transgenic mouse hippocampal neurons that are devoid of pTau accumulation displayed only few GVBs-like vesicles, which were still accompanied by prominent chaperone buildup. Identifying a potential trigger for GVD, we found cytoplasmic accumulations of RBPs including Matrin 3 and FUS as well as stress granules in GVBs of AD patient and pR5 mouse neurons. Interestingly, we observed that GVBs containing aggregated pTau and pTDP-43 were consistently co-localized with the exosomal marker Flotillin 1 in both AD and pR5 mice. In contrast, intraneuronal 82E1-immunoreactive amyloid-beta in human AD and APP/PS1 mice only rarely co-localized with Flotillin 1-positive exosomal vesicles. We conclude that altered chaperone-mediated ER protein homeostasis and impaired autophagy manifesting in GVD are linked to both pTau and RBP accumulation and that some GVBs might be targeted to exocytosis.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Yamoah, Alfred UNSPECIFIED UNSPECIFIED UNSPECIFIED Tripathi, Priyanka UNSPECIFIED UNSPECIFIED UNSPECIFIED Sechi, Antonio UNSPECIFIED UNSPECIFIED UNSPECIFIED Koehler, Christoph UNSPECIFIED UNSPECIFIED UNSPECIFIED Guo, Haihong UNSPECIFIED UNSPECIFIED UNSPECIFIED Chandrasekar, Akila UNSPECIFIED UNSPECIFIED UNSPECIFIED Nolte, Kay Wilhelm UNSPECIFIED UNSPECIFIED UNSPECIFIED Wruck, Christoph Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Katona, Istvan UNSPECIFIED UNSPECIFIED UNSPECIFIED Anink, Jasper UNSPECIFIED UNSPECIFIED UNSPECIFIED Troost, Dirk UNSPECIFIED UNSPECIFIED UNSPECIFIED Aronica, Eleonora UNSPECIFIED UNSPECIFIED UNSPECIFIED Steinbusch, Harry UNSPECIFIED UNSPECIFIED UNSPECIFIED Weis, Joachim UNSPECIFIED UNSPECIFIED UNSPECIFIED Goswami, Anand UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-349854
DOI:	10.3233/JAD-190722
Journal or Publication Title:	J. Alzheimers Dis.
Volume:	75
Number:	1
Page Range:	S. 139 - 157
Date:	2020
Publisher:	IOS PRESS
Place of Publication:	AMSTERDAM
ISSN:	1875-8908
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language AMYOTROPHIC-LATERAL-SCLEROSIS; MARINESCO-SJOGREN-SYNDROME; MILD COGNITIVE IMPAIRMENT; NATIONAL INSTITUTE; NEUROPATHOLOGIC ASSESSMENT; SIGMA-1 RECEPTOR; ASSOCIATION GUIDELINES; DIAGNOSTIC GUIDELINES; DISTAL MYOPATHY; TAU PATHOLOGY Multiple languages Neurosciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/34985