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 -