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Immunohistochemistry staining of somatostatin in the hippocampus. Mosaic reconstruction of the non-AD human hippocampus showing somatostatin distribution (A). In non-AD cases, somatostatin-expressing cells were mainly located in either the stratum oriens in CA regions (B) or within the hilus in the DG (C) and somatostatin fibers were mainly localized to the molecular layers of CA-DG regions (D). The major hallmarks of somatostatin in AD brains were dystrophic neurites (E) and aggregates of fibers and cell debris mainly in the molecular layers of CA (F) and DG (G). CA, cornus amonis; DG, dentate gyrus; Sub, subiculum; so, stratum oriens; sp, stratum piramidale; sl, stratum lacunosum; sr, stratum radiatum; sm, stratum moleculare. Scale bar A, 500 µm; B-G, 160 µm.
Source publication
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease in the elderly. Progressive accumulation of insoluble isoforms of amyloid-β peptide (Aβ) and tau protein are the major neuropathologic hallmarks, and the loss of cholinergic pathways underlies cognitive deficits in patients. Recently, glial involvement has gained interest rega...
Contexts in source publication
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... distribution of SST in the Hip differed between its subfields. While cornu ammonis fields CA1-CA3 contained most SST cell bodies in the stratum oriens ( Figure 3A,B), SST cells within the dentate gyrus (DG) were randomly distributed ( Figure 3A,C). Interestingly, most SST fibers in the Hip localized to the molecular layers of CA1-3 and DG ( Figure 3A,D). ...
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... distribution of SST in the Hip differed between its subfields. While cornu ammonis fields CA1-CA3 contained most SST cell bodies in the stratum oriens ( Figure 3A,B), SST cells within the dentate gyrus (DG) were randomly distributed ( Figure 3A,C). Interestingly, most SST fibers in the Hip localized to the molecular layers of CA1-3 and DG ( Figure 3A,D). ...
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... cornu ammonis fields CA1-CA3 contained most SST cell bodies in the stratum oriens ( Figure 3A,B), SST cells within the dentate gyrus (DG) were randomly distributed ( Figure 3A,C). Interestingly, most SST fibers in the Hip localized to the molecular layers of CA1-3 and DG ( Figure 3A,D). On the other hand, in AD cases, SST-expressing cells commonly presented dystrophic neurites ( Figure 3E). ...
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... most SST fibers in the Hip localized to the molecular layers of CA1-3 and DG ( Figure 3A,D). On the other hand, in AD cases, SST-expressing cells commonly presented dystrophic neurites ( Figure 3E). In addition, the other main feature was the presence of cell debris aggregates. ...
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... addition, the other main feature was the presence of cell debris aggregates. Interestingly, the aggregates were most abundant within the molecular layers of CA-DG ( Figure 3F,G). not vary in the OB or AON when comparing non-AD and AD cases ( Figure 2C,D). ...
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... the pathology linked to Aβ and Tau is mostly associated with SST fibers or released SST, rather than SST-cell bodies. In addition, the molecular layers of CA1 region also exhibited clusters of microglial cells, which frequently colocalized with Aβ, and SST as well (Supplementary Figure S3). This layer also includes the perforant pathway, which contains axonal projections from the entorhinal cortex to the CA1 subregion, among others, and it is involved in early memory loss [27]. ...
Citations
... In this study, our results showed that some limbic system regions altered network topology, including HIP.L, PHG.R, ACG.L, and MCG.R. In a previous histopathological study, the limbic system degenerated in the early stages of AD [50]. Moreover, Pili et al. pointed out that HIP is one of the earliest brain regions to be altered in AD, and that the extent of abnormalities may reflect the disease severity [51]. ...
Alzheimer’s disease (AD) is associated with the abnormal connection of functional networks. Olfactory impairment occurs in early AD; therefore, exploring alterations in olfactory-related regions is useful for early AD diagnosis. We combined the graph theory of local brain network topology with olfactory performance to analyze the differences in AD brain network characteristics. A total of 23 patients with AD and 18 normal controls were recruited for resting-state functional magnetic resonance imaging (fMRI), clinical neuropsychological examinations and the University of Pennsylvania Smell Identification Test (UPSIT). Between-group differences in the topological properties of the local network were compared. Pearson correlations were explored based on differential brain regions and olfactory performance. Statistical analysis revealed a correlation of the degree of cognitive impairment with olfactory recognition function. Local node topological properties were significantly altered in many local brain regions in the AD group. The nodal clustering coefficients of the bilateral temporal pole: middle temporal gyrus (TPOmid), degree centrality of the left insula (INS.L), degree centrality of the right middle temporal gyrus (MTG.R), and betweenness centrality of the left middle temporal gyrus (MTG.L) were related to olfactory performance. Alterations in local topological properties combined with the olfactory impairment can allow early identification of abnormal olfactory-related regions, facilitating early AD screening.
... SST positive inhibitory neurons exert dendritic inhibition to regulate the firing activity of cortical neurons and maintain excitatory-inhibitory signal balance 31 . SST expression is found significantly reduced in the hippocampus of AD patients 32 . SST has been reported to be involved in regulating brain Aβ peptide metabolism and promoting aggregation of Aβ peptides 32,33 . ...
... SST expression is found significantly reduced in the hippocampus of AD patients 32 . SST has been reported to be involved in regulating brain Aβ peptide metabolism and promoting aggregation of Aβ peptides 32,33 . Of note, our finding showed the highest functional similarity score of SST in functional similarity analysis of 9 diagnostic genes. ...
Alzheimer’s disease (AD) is the leading cause of dementia in aged population. Oxidative stress and neuroinflammation play important roles in the pathogenesis of AD. Investigation of hub genes for the development of potential therapeutic targets and candidate biomarkers is warranted. The differentially expressed genes (DEGs) in AD were screened in GSE48350 dataset. The differentially expressed oxidative stress genes (DEOSGs) were analyzed by intersection of DEGs and oxidative stress-related genes. The immune-related DEOSGs and hub genes were identified by weighted gene co-expression network analysis (WGCNA) and protein–protein interaction (PPI) analysis, respectively. Enrichment analysis was performed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. The diagnostic value of hub genes was assessed by receiver operating characteristic analysis and validated in GSE1297. The mRNA expression of diagnostic genes was determined by qRT-PCR analysis. Finally, we constructed the drug, transcription factors (TFs), and microRNA network of the diagnostic genes. A total of 1160 DEGs (259 up-regulated and 901 down-regulated) were screened in GSE48350. Among them 111 DEOSGs were identified in AD. Thereafter, we identified significant difference of infiltrated immune cells (effector memory CD8 T cell, activated B cell, memory B cell, natural killer cell, CD56 bright natural killer cell, natural killer T cell, plasmacytoid dendritic cell, and neutrophil) between AD and control samples. 27 gene modules were obtained through WGCNA and turquoise module was the most relevant module. We obtained 66 immune-related DEOSGs by intersecting turquoise module with the DEOSGs and identified 15 hub genes through PPI analysis. Among them, 9 hub genes (CCK, CNR1, GAD1, GAP43, NEFL, NPY, PENK, SST, and TAC1) were identified with good diagnostic values and verified in GSE1297. qRT-PCR analysis revealed the downregulation of SST, NPY, GAP43, CCK, and PENK and upregulation of NEFL in AD. Finally, we identified 76 therapeutic agents, 152 miRNAs targets, and 91 TFs regulatory networks. Our study identified 9 key genes associated with oxidative stress and immune reaction in AD pathogenesis. The findings may help to provide promising candidate biomarkers and therapeutic targets for AD.
... Chronic leptin treatment of transgenic mice overexpressing amyloid precursor protein (APP) reduced brain concentrations of Aβ and phosphorylated tau, improving memory [117], and acute central leptin infusion increased brain somatostatin [118] with a concomitant uprising of CREB, involved in memory processes. Somatostatin is a neuropeptide involved in cognitive processes and is reduced in the hippocampus of experimental models of AD [119] and in AD patients [120]. Moreover, chronic central leptin treatment reduces Aβ-mediated impairment in memory and suppression of hippocampal LTP [121]. ...
Excess body weight is frequently associated with low-grade inflammation. Evidence indicates a relationship between obesity and cancer, as well as with other diseases, such as diabetes and non-alcoholic fatty liver disease, in which inflammation and the actions of various adipokines play a role in the pathological mechanisms involved in these disorders. Leptin is mainly produced by adipose tissue in proportion to fat stores, but it is also synthesized in other organs, where leptin receptors are expressed. This hormone performs numerous actions in the brain, mainly related to the control of energy homeostasis. It is also involved in neurogenesis and neuroprotection, and central leptin resistance is related to some neurological disorders, e.g., Parkinson’s and Alzheimer’s diseases. In peripheral tissues, leptin is implicated in the regulation of metabolism, as well as of bone density and muscle mass. All these actions can be affected by changes in leptin levels and the mechanisms associated with resistance to this hormone. This review will present recent advances in the molecular mechanisms of leptin action and their underlying roles in pathological situations, which may be of interest for revealing new approaches for the treatment of diseases where the actions of this adipokine might be compromised.
... Recently, it has been shown that sleep deprivation could selectively activate somatostatin-expressing interneurons and disrupts hippocampus based contextual fear conditioning in mice [83]. Gonzalez-Rodriguez et al. have recently reported that somatostatin-expressing cells are highly reduced in the human hippocampus and might be involved in AD pathogenesis [84]. ...
Poor quality and quantity of sleep are very common in elderly people throughout the world. Growing evidence has suggested that sleep disturbances could accelerate the process of neurodegeneration. Recent reports have shown a positive correlation between sleep deprivation and amyloid-β (Aβ)/tau aggregation in the brain of Alzheimer’s patients. Glial cells have long been implicated in the progression of Alzheimer’s disease (AD) and recent findings have also suggested their role in regulating sleep homeostasis. However, how glial cells control the sleep–wake balance and exactly how disturbed sleep may act as a trigger for Alzheimer’s or other neurological disorders have recently gotten attention. In an attempt to connect the dots, the present review has highlighted the role of glia-derived sleep regulatory molecules in AD pathogenesis.
Graphical Abstract
Role of glia in sleep disturbance and Alzheimer’s progression.
... Changes in somatostatin content in the cerebral cortex, especially in the temporal lobe, are a hallmark of Alzheimer's disease [138] and a decrease in the number of SOM-INs was observed in temporal lobe brain samples from patients [139,140]. In the hippocampus, the number of SOM-expressing cells was reduced by 50% [141] and SOM receptors were also reduced in the temporal cortex of patients with AD [142]. In murine models of Alzheimer's disease in which protein deposits built up, atrophy and synaptic SOM-INs abnormalities have been observed [99,143]. ...
Despite the obvious differences in the pathophysiology of distinct neuropsychiatric diseases or neurodegenerative disorders, some of them share some general but pivotal mechanisms, one of which is the disruption of excitation/inhibition balance. Such an imbalance can be generated by changes in the inhibitory system, very often mediated by somatostatin-containing interneurons (SOM-INs). In physiology, this group of inhibitory interneurons, as well as somatostatin itself, profoundly shapes the brain activity, thus influencing the behavior and plasticity; however, the changes in the number, density and activity of SOM-INs or levels of somatostatin are found throughout many neuropsychiatric and neurological conditions, both in patients and animal models. Here, we (1) briefly describe the brain somatostatinergic system, characterizing the neuropeptide somatostatin itself, its receptors and functions, as well the physiology and circuitry of SOM-INs; and (2) summarize the effects of the activity of somatostatin and SOM-INs in both physiological brain processes and pathological brain conditions, focusing primarily on learning-induced plasticity and encompassing selected neuropsychological and neurodegenerative disorders, respectively. The presented data indicate the somatostatinergic-system-mediated inhibition as a substantial factor in the mechanisms of neuroplasticity, often disrupted in a plethora of brain pathologies.
Purpose/aim of the study:
Heavy metals and metalloids have been implicated in neurodenerative diseases. Present study has evaluated the potential protective effects of Se and Zn on heavy metals and metalloids mixture-induced (Cd, Pb, Hg and As) toxicity in the hippocampus and olfactory bulb in male rats.
Materials and methods:
Five groups of Wistar rats were randomly divided in to: controls, toxic metals mixture (TMM) exposed rats (PbCl2, 20 mg·kg-1; CdCl2, 1.61 mg·kg-1; HgCl2, 0.40 mg·kg-1 and NaAsO3, 10 mg·kg-1)), TMM + Zn, TMM + Se and TMM-+Zn + Se groups and were orally treated for 60 days.
Results:
We found that in hippocampus and olfactory bulb, TMM generated increased lipid peroxidation and diminished antioxidant capacity. These adverse effects induced by TMM were alleviated by Zn and Se co-treatment; moreover, essential trace elements (Zn and Se) decreased activity of acetylcholinesterase, reduced Cd, Pb, Hg and As bioaccumulation in hippocampus and olfactory bulb and decreased levels of TNF-α in the hippocampus. TMM treated rats had lower levels of Hmox-1 (hippocampus), higher levels of Nrf2 (olfactory bulb and hippocampus) and NF-kB (olfactory bulb). TMM treated rats showed significantly highest time in locating the escape hole. Histopathological examination revealed hypertrophied granule cells in OB of TMM exposed rats.
Conclusion:
Zn and Se supplementation can reverse quaternary mixture-induced (Cd, Pb, Hg and As) toxicity in hippocampus and OB in male albino rats.
