Somatostatin and Alzheimer's disease

Burgos‐Ramos, Emma; Hervás-Aguilar, América; Aguado-Llera, David; Puebla‐Jiménez, L.; Hernández‐Pinto, Alberto M.; Barrios, Vicente; Arilla‐Ferreiro, Eduardo

doi:10.1016/j.mce.2008.01.014

Cited by 78 publications

(48 citation statements)

References 112 publications

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“…These authors suggest that such variations to be related not only to the more complex architecture in basal dendrites versus apical dendrites but also to the distribution of GABAergic interneurons in specific regions of the hippocampus (Jinno and Kosaka, 2000;Cope et al, 2002;Pawelzik et al, 2002). The idea of a local network dysfunction in the hippocampus of AD patients has been repeatedly suggested (for review, see Burgos-Ramos et al, 2008). Somatostatin, calretinin, and parvalbumin are all markers of GABAergic interneurons in the hippocampus, and they have been used to demonstrate impairment in aged rats by a reduced number of labeled neurons (Vela et al, 2003;Gavilan et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Reduced Spine Density in Specific Regions of CA1 Pyramidal Neurons in Two Transgenic Mouse Models of Alzheimer's Disease

Pérez-Cruz¹,

Nolte²,

Gaalen³

et al. 2011

J. Neurosci.

157

120

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One major hallmark of Alzheimer's disease (AD) is the massive loss of synapses that occurs at an early clinical stage of the disease. In this study, we characterize alterations in spine density and the expression of synapse-associated immediate early gene Arc (activity-regulated cytoskeleton-associated protein) in the hippocampal CA1 regions of two different amyloid precursor protein (APP) transgenic mouse lines before plaque development and their connection to performance in hippocampus-dependent memory tests. The density of mushroom-type spines was reduced by 34% in the basal dendrites proximal to the soma of CA1 pyramidal neurons in 5.5-month-old Tg2576 mice, carrying the Swedish mutation, compared with wild-type littermates. A similar reduction of 42% was confirmed in the same region of 8-month-old APP/Lo mice, carrying the London mutation. In this strain, the reduction extended to the distal dendritic spines (28%), although no differences were found in apical dendrites in either transgenic mouse line. Both transgenic mice lines presented a significant increase in Arc protein expression in CA1 compared with controls, suggesting rather an overactivity and increased spine turnover that was supported by a significant decrease in number of somatostatin-immunopositive inhibitory interneurons in the stratum oriens of CA1. Behaviorally, the transgenic mice showed decrease freezing in the fear contextual conditioning test and impairment in spatial memory assessed by Morris water maze test. These data indicate that cognitive impairment in APP transgenic mice is correlated with impairment of synaptic connectivity in hippocampal CA1, probably attributable to loss of inhibitory interneurons and subsequent hyperactivity.

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Section: Discussionmentioning

confidence: 99%

Reduced Spine Density in Specific Regions of CA1 Pyramidal Neurons in Two Transgenic Mouse Models of Alzheimer's Disease

Pérez-Cruz¹,

Nolte²,

Gaalen³

et al. 2011

J. Neurosci.

157

120

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“…Cilia extruding into the extracellular space are coated with SST 3 , suggesting they are sensitive detectors of increases in SST levels such as would occur during high-frequency neuronal firing (Fanselow et al, 2008). Decreased SST levels found in hippocampus and cortex in Alzheimer's disease (Burgos-Ramos et al, 2008) could contribute to deficits in recognition memory in these patients. Thus, SST 3 could be a novel target in treatment of dementia and other types of cognitive impairment.…”

Section: Discussionmentioning

confidence: 99%

“…SST expression in cortex and hippocampus is significantly reduced in Alzheimer's disease, and this reduction is correlated with cognitive decline, suggesting this peptide may be critical in cognitive processing (Burgos-Ramos et al, 2008). Previous studies examining the role of SST in learning and memory have produced conflicting results, suggesting both facilitating and inhibitory actions on learning and memory (Baraban and Tallent, 2004).…”

Section: Introductionmentioning

confidence: 99%

Somatostatin Signaling in Neuronal Cilia Is Criticalfor Object Recognition Memory

Einstein¹,

Patterson²,

Hon³

et al. 2010

J. Neurosci.

107

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Most neurons possess a single, nonmotile cilium that projects out from the cell surface. These microtubule-based organelles are important in brain development and neurogenesis; however, their function in mature neurons is unknown. Cilia express a complement of proteins distinct from other neuronal compartments, one of which is the somatostatin receptor subtype SST 3 . We show here that SST 3 is critical for object recognition memory in mice. sst3 knock-out mice are severely impaired in discriminating novel objects, whereas they retain normal memory for object location. Further, systemic injection of an SST 3 antagonist (ACQ090) disrupts recall of familiar objects in wild-type mice. To examine mechanisms of SST 3 , we tested synaptic plasticity in CA1 hippocampus. Electrically evoked long-term potentiation (LTP) was normal in sst3 knock-out mice, while adenylyl cyclase/cAMP-mediated LTP was impaired. The SST 3 antagonist also disrupted cAMP-mediated LTP. Basal cAMP levels in hippocampal lysate were reduced in sst3 knock-out mice compared with wild-type mice, while the forskolin-induced increase in cAMP levels was normal. The SST 3 antagonist inhibited forskolin-stimulated cAMP increases, whereas the SST 3 agonist L-796,778 increased basal cAMP levels in hippocampal slices but not hippocampal lysate. Our results show that somatostatin signaling in neuronal cilia is critical for recognition memory and suggest that the cAMP pathway is a conserved signaling motif in cilia. Neuronal cilia therefore represent a novel nonsynaptic compartment crucial for signaling involved in a specific form of synaptic plasticity and in novelty detection.

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“…While this is happening, the pro-NGF-activated axonal p75 NTR •sortilin complexes induced by the accumulating Aβ 1-42 start killing BFCSNs and cutting off the hippocampal supply of ACh [3]. Also counter-intuitively despite the increased Aβ 1 -42 /p75 NTR -driven progenitor cell proliferation, neurogenesis is not increased because fewer TA neurons can survive without the support of ACh and because the cilial SSTR3 receptors needed for maturation and memory functions [20] are silenced by the lack of SST in AD brains [21] (Figure 2) In conclusion, cilial p75 NTR must now be part of models of adult neurogenesis in the DGy and memory formation and of the cognitive decline in aging and AD brains. NTR , the signals from which can stimulate granule cell progenitor proliferation, and also with SSTR3 (not shown), the signals from which can drive the postmitotic maturation of newborn neurons.…”

Section: Figurementioning

confidence: 99%

A Paradigm-Changing Surprise from Dentate Gyrus Granule Cells— Cilium-Localized p75NTR May Drive Their Progenitor Cell Proliferation

Armato¹,

Chakravarthy²,

Chiarini³

et al. 2011

J Alzheimers Dis

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The dentate gyrus (DGy) is made up mainly of granule neurons (GNs) with interspersed GABAergic interneurons. The subgranular zone (SGZ) of the DGy is one of the two main sites of neurogenesis (the subventricular zone [SVZ] is the other) in adult mice and humans being inhabited by progenitor granular cells and their transit amplifying (TA) progeny [1,2]. The GNs and hilar neurons produce neuro-trophins, such as brain-derived neuro-trophic factor (BDNF), nerve growth factor (NGF) and neuro-trophin-3 (NT-3), which selectively activate different Trk-family receptors [3]. The signals from these receptors attract receptor-bearing axons from basal forebrain cholinergic septal neurons (BFCSNs) to extend along the septo-hippocampal pathway and terminate on dendrites of neurons residing in the DGy molecular layer [4][5][6]. The BFCSNs axons terminate mainly in the inner molecular layer and the hilus, but not in the GNs layer [6]. The progenitor and TA neurons in the SGZ are in synaptic contact with the cholinergic axons of the BFCSNs and they express acetylcholine (Ach) receptors, which enable them to respond to the local diffuse availability of ACh [4]. The BFCSN axons release Ach, which promotes progenitor neuron proliferation as well as the survival and maturation of TA neurons in the SGZ. Conversely, inhibiting ACh activity or selectively killing BFCSNs with the monoclonal anti-NGF 192 IgG antibody-saporin immunotoxin inhibits the SGZ production of new neurons [4,7] (Figures 1 and 2).

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Somatostatin and Alzheimer's disease

Cited by 78 publications

References 112 publications

Reduced Spine Density in Specific Regions of CA1 Pyramidal Neurons in Two Transgenic Mouse Models of Alzheimer's Disease

Reduced Spine Density in Specific Regions of CA1 Pyramidal Neurons in Two Transgenic Mouse Models of Alzheimer's Disease

Somatostatin Signaling in Neuronal Cilia Is Criticalfor Object Recognition Memory

A Paradigm-Changing Surprise from Dentate Gyrus Granule Cells— Cilium-Localized p75NTR May Drive Their Progenitor Cell Proliferation

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