Critical role of somatostatin receptor 2 in the vulnerability of the central noradrenergic system: new aspects on Alzheimer’s disease

C. Ádori, Laura Glück, Swapnali Barde, Takashi Yoshitake, Gabor G. Kovacs, Jan Mulder, Z. Maglóczky, László Havas, K. Bölcskei, Nicholas Mitsios, Mathias Uhlén, J. Szolcsányi, Jan Kehr, Annica Rönnbäck, Thue Schwartz, Jens F. Rehfeld, Tibor Harkany, M. Palkóvits, Stefan Schulz, Tomas Hökfelt

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Alzheimer’s 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 deficit in the maintenance of noradrenergic projections remains unknown. Here, we deployed tissue microarrays, immunohistochemistry, quantitative morphometry and mRNA profiling in a cohort of Alzheimer’s and age-matched control brains in combination with genetic models of somatostatin receptor deficiency to establish causality between defunct somatostatin signalling and noradrenergic neurodegeneration. In Alzheimer’s disease, we found significantly 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 significantly decreasing from Braak stages III/IV and onwards, i.e., a process preceding advanced Alzheimer’s pathology. The loss of SSTR2 transcripts in the LC neurons appeared selective, since tyrosine hydroxylase, dopamine β-hydroxylase, galanin or galanin receptor 3 mRNAs remained unchanged. We modeled these pathogenic changes in Sstr2−/− mice and, unlike in Sstr1−/− or Sstr4−/− genotypes, they showed selective, global and progressive degeneration of their central noradrenergic projections. However, neuronal perikarya in the LC were found intact until late adulthood (−/− mice. In contrast, the noradrenergic neurons in the superior cervical ganglion lacked SSTR2 and, as expected, the sympathetic innervation of the head region did not show any signs of degeneration. Our results indicate that SSTR2-mediated signaling is integral to the maintenance of central noradrenergic projections at the system level, and that early loss of somatostatin receptor 2 function may be associated with the selective vulnerability of the noradrenergic system in Alzheimer’s disease.

Original languageEnglish
Pages (from-to)541-563
Number of pages23
JournalActa Neuropathologica
Volume129
Issue number4
DOIs
Publication statusPublished - Apr 1 2015

Fingerprint

Locus Coeruleus
Somatostatin
Alzheimer Disease
Adrenergic Neurons
Tyrosine 3-Monooxygenase
Receptor, Galanin, Type 3
Messenger RNA
Maintenance
Pathology
Galanin
Superior Cervical Ganglion
Somatostatin Receptors
Genetic Models
Temporal Lobe
Mixed Function Oxygenases
Causality
Neurodegenerative Diseases
Cluster Analysis
Dopamine
Immunohistochemistry

Keywords

  • Alzheimer’s disease
  • Co-existence
  • Depression
  • Neurodegeneration
  • Neuropeptide
  • Neurotransmitter
  • Noradrenaline

ASJC Scopus subject areas

  • Clinical Neurology
  • Pathology and Forensic Medicine
  • Cellular and Molecular Neuroscience

Cite this

Critical role of somatostatin receptor 2 in the vulnerability of the central noradrenergic system : new aspects on Alzheimer’s disease. / Ádori, C.; Glück, Laura; Barde, Swapnali; Yoshitake, Takashi; Kovacs, Gabor G.; Mulder, Jan; Maglóczky, Z.; Havas, László; Bölcskei, K.; Mitsios, Nicholas; Uhlén, Mathias; Szolcsányi, J.; Kehr, Jan; Rönnbäck, Annica; Schwartz, Thue; Rehfeld, Jens F.; Harkany, Tibor; Palkóvits, M.; Schulz, Stefan; Hökfelt, Tomas.

In: Acta Neuropathologica, Vol. 129, No. 4, 01.04.2015, p. 541-563.

Research output: Contribution to journalArticle

Ádori, C, Glück, L, Barde, S, Yoshitake, T, Kovacs, GG, Mulder, J, Maglóczky, Z, Havas, L, Bölcskei, K, Mitsios, N, Uhlén, M, Szolcsányi, J, Kehr, J, Rönnbäck, A, Schwartz, T, Rehfeld, JF, Harkany, T, Palkóvits, M, Schulz, S & Hökfelt, T 2015, 'Critical role of somatostatin receptor 2 in the vulnerability of the central noradrenergic system: new aspects on Alzheimer’s disease', Acta Neuropathologica, vol. 129, no. 4, pp. 541-563. https://doi.org/10.1007/s00401-015-1394-3
Ádori, C. ; Glück, Laura ; Barde, Swapnali ; Yoshitake, Takashi ; Kovacs, Gabor G. ; Mulder, Jan ; Maglóczky, Z. ; Havas, László ; Bölcskei, K. ; Mitsios, Nicholas ; Uhlén, Mathias ; Szolcsányi, J. ; Kehr, Jan ; Rönnbäck, Annica ; Schwartz, Thue ; Rehfeld, Jens F. ; Harkany, Tibor ; Palkóvits, M. ; Schulz, Stefan ; Hökfelt, Tomas. / Critical role of somatostatin receptor 2 in the vulnerability of the central noradrenergic system : new aspects on Alzheimer’s disease. In: Acta Neuropathologica. 2015 ; Vol. 129, No. 4. pp. 541-563.
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AU - Yoshitake, Takashi

AU - Kovacs, Gabor G.

AU - Mulder, Jan

AU - Maglóczky, Z.

AU - Havas, László

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AU - Mitsios, Nicholas

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AU - Szolcsányi, J.

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AU - Rehfeld, Jens F.

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