title: Critical role of somatostatin receptor 2 in the vulnerability of the central noradrenergic system: new aspects on Alzheimer's disease.
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 (<8 months) in Sstr2(-/-) 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.
authors: Department of Neuroscience, Retzius Laboratory, Karolinska Institutet, Retzius väg 8, 17177, Stockholm, Sweden, adorics@gmail.com.
authors: Csaba
authors: C
authors: Ádori
authors: Laura
authors: L
authors: Glück
authors: Swapnali
authors: S
authors: Barde
authors: Takashi
authors: T
authors: Yoshitake
authors: Gabor G
authors: GG
authors: Kovacs
authors: Jan
authors: J
authors: Mulder
authors: Zsófia
authors: Z
authors: Maglóczky
authors: László
authors: L
authors: Havas
authors: Kata
authors: K
authors: Bölcskei
authors: Nicholas
authors: N
authors: Mitsios
authors: Mathias
authors: M
authors: Uhlén
authors: János
authors: J
authors: Szolcsányi
authors: Jan
authors: J
authors: Kehr
authors: Annica
authors: A
authors: Rönnbäck
authors: Thue
authors: T
authors: Schwartz
authors: Jens F
authors: JF
authors: Rehfeld
authors: Tibor
authors: T
authors: Harkany
authors: Miklós
authors: M
authors: Palkovits
authors: Stefan
authors: S
authors: Schulz
authors: Tomas
authors: T
authors: Hökfelt
mesh_terms: D000367:Age Factors; D000368:Aged; D000544:Alzheimer Disease / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism; D002232:Carbocyanines / Q000378:metabolism; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008125:Locus Coeruleus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D017481:Receptors, Somatostatin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013004:Somatostatin / Q000378:metabolism; D013702:Temporal Lobe / Q000378:metabolism / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D015306:Biogenic Monoamines; D002232:Carbocyanines; D017481:Receptors, Somatostatin; C098830:TO-PRO-3; D016875:tau Proteins; D013004:Somatostatin; C093733:somatostatin receptor 2; D014446:Tyrosine 3-Monooxygenase; D009638:Norepinephrine