Critical role of somatostatin receptor 2 in the vulnerability of the central noradrenergic system: new aspects on Alzheimer's disease
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Critical role of somatostatin receptor 2 in the vulnerability of the central noradrenergic system : new aspects on Alzheimer's disease. / Ádori, Csaba; Glück, Laura; Barde, Swapnali; Yoshitake, Takashi; Kovacs, Gabor G; Mulder, Jan; Maglóczky, Zsófia; Havas, László; Bölcskei, Kata; Mitsios, Nicholas; Uhlén, Mathias; Szolcsányi, János; Kehr, Jan; Rönnbäck, Annica; Schwartz, Thue; Rehfeld, Jens F; Harkany, Tibor; Palkovits, Miklós; Schulz, Stefan; Hökfelt, Tomas.
I: Acta Neuropathologica, Bind 129, Nr. 4, 04.2015, s. 541-63.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Critical role of somatostatin receptor 2 in the vulnerability of the central noradrenergic system
T2 - new aspects on Alzheimer's disease
AU - Ádori, Csaba
AU - Glück, Laura
AU - Barde, Swapnali
AU - Yoshitake, Takashi
AU - Kovacs, Gabor G
AU - Mulder, Jan
AU - Maglóczky, Zsófia
AU - Havas, László
AU - Bölcskei, Kata
AU - Mitsios, Nicholas
AU - Uhlén, Mathias
AU - Szolcsányi, János
AU - Kehr, Jan
AU - Rönnbäck, Annica
AU - Schwartz, Thue
AU - Rehfeld, Jens F
AU - Harkany, Tibor
AU - Palkovits, Miklós
AU - Schulz, Stefan
AU - Hökfelt, Tomas
PY - 2015/4
Y1 - 2015/4
N2 - 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.
AB - 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.
KW - Age Factors
KW - Aged
KW - Alzheimer Disease
KW - Amyloid beta-Peptides
KW - Animals
KW - Biogenic Monoamines
KW - Carbocyanines
KW - Case-Control Studies
KW - Cohort Studies
KW - Female
KW - Gene Expression Regulation
KW - Humans
KW - Locus Coeruleus
KW - Male
KW - Mice
KW - Mice, Transgenic
KW - Middle Aged
KW - Neurons
KW - Norepinephrine
KW - Receptors, Somatostatin
KW - Signal Transduction
KW - Somatostatin
KW - Temporal Lobe
KW - Tyrosine 3-Monooxygenase
KW - tau Proteins
U2 - 10.1007/s00401-015-1394-3
DO - 10.1007/s00401-015-1394-3
M3 - Journal article
C2 - 25676386
VL - 129
SP - 541
EP - 563
JO - Acta Neuropathologica
JF - Acta Neuropathologica
SN - 0001-6322
IS - 4
ER -
ID: 160478371