Cognitive decline in STZ-3V rats is largely due to dysfunctional insulin signalling through the dentate gyrus

Shingo, Akiko; Kanabayashi, Tomomichi; Kito, Shozo

doi:10.1016/j.bbr.2012.01.034

Cited by 48 publications

(18 citation statements)

References 33 publications

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“…Looking from this perspective, our results are complementary to the previously published data (Correia et al 2013, Shingo et al 2012. Namely, intracellular Aβ 1-42 accumulation in the rat brain as early as few weeks after the STZ-icv administration might be generated as the acute compensatory effect whose detection could be related to its intensity (depending on a STZ-icv dose), the method and Aβ 1-42 antibody used.…”

Section: Discussionsupporting

confidence: 84%

“…To the best of our knowledge, this is the first morphological evidence of generation of diffuse plaque-like accumulation of Aβ 1-42 in the brain of non-transgenic rodents. Positive (non-aggregated) Aβ 1-42 signal in other studies was detected before 3 months but after the treatment with STZ-icv doses 13x higher (40 mg/kg; Shingo et al 2012Shingo et al , 2013, which makes comparison with our data difficult.…”

Section: Discussioncontrasting

confidence: 75%

“…Severely affected STZ-icv rats also demonstrate extensive cell loss, inferred from increase in the volume of the ventricular system (Kraska et al 2012;Prickaerts et al 2000;Shoham et al 2003), and a significant enlargement of the trans-Golgi compartment in cortical neurons at the ultrastructural level (Grieb et al 2004). In addition, increased Aβ 1-42 and hyperphosphorylated tau immunoreactivity have been detected in the hippocampus of STZ-icv rats and mice (Chen et al 2013;Correia et al 2013;Deng et al 2009;Kosaraju et al 2013;Shingo et al 2012). Accumulation of Aβ in the cerebral microvasculature (cerebral amyloid angiopathy, CAA) has been observed first in the meningeal capillaries (SalkovicPetrisic et al 2006), progressing subsequently to the intracortical blood vessels of STZ-icv rats (Salkovic-Petrisic et al 2011).…”

Section: Introductionmentioning

confidence: 99%

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Staging of cognitive deficits and neuropathological and ultrastructural changes in streptozotocin-induced rat model of Alzheimer’s disease

et al. 2015

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Immunohistochemistry and electron microscopy analysis were used to detect amyloid β-(Aβ 1-42 ) and hyperphosphorylated tau (AT8) accumulation and ultrastructural changes in the brain. Memory decline was time-(≤3 months/acute, ≥3 months/progressive) and STZ-icv dosedependent. Morphological changes were manifested as thinning of parietal cortex (≥1 month) and corpus callosum (9 months), and were more pronounced in the 3 mg/kg STZ group. Early neurofibrillary changes (AT8) were detected from 1 month onward in the neocortex, and progressed after 3 months to the hippocampus. Intracellular Aβ 1-42 accumulation was found in the neocortex at 3 months following STZ-icv treatment, while diffuse Aβ 1-42 -positive plaque-like formations were found after 6 months in the neocortex and hippocampus. Ultrastructural changes revealed enlargement of Golgi apparatus, pyknotic nuclei, and timedependent increase in lysosome size, number, and density. Our data provide a staging of cognitive, structural/ultrastructural, and neuropathological markers in the STZ-icv rat model that in many aspects seems to be generally comparable to stages seen in human sAD.

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Section: Discussionsupporting

confidence: 84%

Section: Discussioncontrasting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

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Staging of cognitive deficits and neuropathological and ultrastructural changes in streptozotocin-induced rat model of Alzheimer’s disease

et al. 2015

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“…Thus, STZ may contribute to memory and learning disorders in male Wistar rats. The dose of STZ used in this study is safe and has been shown not to cause any change in peripheral blood glucose levels [22] . In previous studies, the effect of testosterone on rats treated with STZ in relation to androgen or estrogen receptors has not been thoroughly addressed [23] .…”

Section: Resultsmentioning

confidence: 82%

Testosterone ameliorates streptozotocin-induced memory impairment in male rats

2014

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Aim: To study the effects of testosterone on streptozotocin (STZ)-induced memory impairment in male rats. Methods: Adult male Wistar rats were intracerebroventricularly (icv) infused with STZ (750 µg) on d 1 and d 3, and a passive avoidance task was assessed 2 weeks after the first injection of STZ. Castration surgery was performed in another group of rats, and the passive avoidance task was assessed 4 weeks after the operation. , ip) were administered for 6 d after the first injection of STZ. Results: STZ administration and castration markedly decreased both STL1 (the short memory) and STL2 (the long memory) in passive avoidance tests. Testosterone replacement almost restored the STL1 and STL2 in castrated rats, and significantly prolonged the STL1 and STL2 in STZ-treated rats. Administration of flutamide, letrozole or tamoxifen significantly impaired the memory in intact rats, and significantly attenuated the testosterone replacement in improving STZ-and castration-induced memory impairment. Conclusion: Testosterone administration ameliorates STZ-and castration-induced memory impairment in male Wistar rats.

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“…AD is associated with reduced insulin and insulin mRNA as well as decrease level of insulin receptors [66]. In vitro, studies have shown the impaired insulin signalling, hyperphosphorylated tau proteins, and neural loss in T2DM affected AD animal models [129][130][131][132].…”

Section: Insulin Resistance In Peripheral System and Central Nervous mentioning

confidence: 99%

Metabolic study of Alzheimer’s disease using mutant C. elegans

Ahmad¹

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Alzheimer's disease (AD) is associated with chronic neurodegeneration and is the cause of the most common form of dementia. The main hallmarks of AD are aggregates of amyloid beta (Aβ) and formation of hyperphosphorylated tau neurofibrillary tangles (NFTs). Unfortunately, after more than 100 years of research the exact cause(s) and mechanisms involved in AD progression remain unclarified. Evidence indicates that impaired mitochondrial bioenergetics may precede by decades, the neurodegeneration and cognitive decline associated with AD. Moreover, a genetic association of the core metabolic enzyme dihydrolipoamide dehydrogenase (DLD) with late-onset AD and reduced activity of DLD-containing enzymes suggests glucose hypo-metabolism as a possible cause of AD. Contrary to this, improvements of AD symptoms under caloric restriction or other means of reducing-glucose dependent energy metabolism supports an alternative hypothesis that a decrease in glucose metabolism may be protective. In the present study, we used mutant Caenorhabditis elegans (C. elegans) to investigate the effect of glucose metabolism on AD progression. We initially looked at the role of suppressed DLD-1, and then we focused on the effect of high glucose in AD pathogenesis.Transgenic expression of Aβ in C. elegans causes both phenotypic and behavioral defects and results in accumulation of toxic Aβ oligomers, culminating in protein aggregation as is normally associated with AD pathophysiology. Aβ expression in worm muscle causes agedependent progressive paralysis and impaired acetylcholine neurotransmission while neuronal Aβ expression results in defective chemotaxis and impaired serotonin sensitivity as well as reduced fecundity and egg hatching. Suppression of the dld-1 gene alleviated paralysis, improved acetylcholine neurotransmission, enhanced chemotaxis and restored normal sensitivity to serotonin.dld-1 gene suppression also protects vitality as indicated by improved fecundity and egg hatching.Interestingly, protective effects of dld-1 suppression could be reversed using the calcium ionophore (CaI), indicating that the protective mechanism involves calcium signaling. Each of these beneficial effects of dld-1 gene suppression could be mimicked using a specific, small molecule inhibitor of the DLD-1 enzyme, 5-methoxyindole-2-carboxylic acid (MICA).High glucose levels are associated with the metabolic disorder, diabetes, which is a major risk factor for AD. In fact, it has been suggested that AD is a neural form of diabetes, type 3 diabetes. If true, drugs used to treat diabetes could act as possible treatments for AD. In this study, I investigated the effect of elevated glucose, the glucose metabolism inhibitor, 2-deoxy-d-glucose ii (2DOG) as well as the anti-diabetes drugs, metformin and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), on AD progression. Elevated glucose in the growth medium induced hyperactivity, which interfered with the paralysis assays, but it was seen to impair cholinergic neurotransmission, egg laying and hatc...

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Cognitive decline in STZ-3V rats is largely due to dysfunctional insulin signalling through the dentate gyrus

Cited by 48 publications

References 33 publications

Staging of cognitive deficits and neuropathological and ultrastructural changes in streptozotocin-induced rat model of Alzheimer’s disease

Staging of cognitive deficits and neuropathological and ultrastructural changes in streptozotocin-induced rat model of Alzheimer’s disease

Testosterone ameliorates streptozotocin-induced memory impairment in male rats

Metabolic study of Alzheimer’s disease using mutant C. elegans

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