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Acta Neuropathol (2015) 129:541563 DOI 10.1007/s00401-015-1394-3
ORIGINAL PAPER
Critical role of somatostatin receptor 2 in the vulnerability of the central noradrenergic system: new aspects on Alzheimers disease
Csaba dori Laura Glck Swapnali Barde Takashi Yoshitake Gabor G. Kovacs Jan Mulder Zsa Maglczky Lszl Havas Kata Blcskei Nicholas Mitsios Mathias Uhln Jnos Szolcsnyi Jan Kehr Annica Rnnbck Thue Schwartz Jens F. Rehfeld Tibor Harkany Mikls Palkovits Stefan Schulz Tomas Hkfelt
Received: 16 December 2014 / Revised: 23 January 2015 / Accepted: 23 January 2015 / Published online: 13 February 2015 Springer-Verlag Berlin Heidelberg 2015
Alzheimers and age-matched control brains in combination with genetic models of somatostatin receptor deciency to establish causality between defunct somatostatin signalling and noradrenergic neurodegeneration.In Alzheimers disease, we found signicantly reduced somatostatin protein expression in the temporal cortex, with aberrant clustering and bulging of tyrosine hydroxylase-immunoreactive afferents. As such, somatostatin receptor 2 (SSTR2) mRNA was highly expressed in the human LC, with its levels signicantly decreasing from Braak stages III/IV and onwards, i.e., a process preceding advanced Alzheimers pathology. The loss of SSTR2 transcripts in the LC neurons appeared selective, since tyrosine hydroxylase, dopamine -hydroxylase, galanin or galanin receptor 3 mRNAs remained unchanged. We
Abstract Alzheimers disease and other age-related neurodegenerative disorders are associated with deterioration of the noradrenergic locus coeruleus (LC), a probable trigger for mood and memory dysfunction. LC noradrenergic neurons exhibit particularly high levels of somatostatin binding sites. This is noteworthy since cortical and hypothalamic somatostatin content is reduced in neurodegenerative pathologies. Yet a possible role of a somatostatin signal decit in the maintenance of noradrenergic projections remains unknown. Here, we deployed tissue microarrays, immunohistochemistry, quantitative morphometry and mRNA proling in a cohort of
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C. dori (*) S. Barde J. Mulder N. Mitsios T. Hkfelt (*) Department of Neuroscience, Retzius Laboratory, Karolinska Institutet, Retzius vg 8, 17177 Stockholm, Swedene-mail: [email protected]; [email protected]
T. Hkfelte-mail: [email protected]
L. Glck S. Schulz
Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller University, 07747 Jena, Germany
T. Yoshitake J. Kehr
Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden
G. G. Kovacs
Institute of Neurology, Medical University of Vienna, 1097 Vienna,...