Dysregulation of the mTOR Pathway Mediates Impairment of Synaptic Plasticity in a Mouse Model of Alzheimer's Disease

Ma, Tao; Hoeffer, Charles A.; Capetillo-Zárate, Estibaliz; Yu, Fangmin; Wong, Helen; Lin, Michael; Tampellini, Davide; Klann, Eric; Blitzer, Robert D.; Gouras, Gunnar K.

doi:10.1371/journal.pone.0012845

Cited by 219 publications

(213 citation statements)

References 48 publications

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“…Indeed, inhibition of GSK3b, a downstream target of PI 3-kinase, prevents inhibition of hippocampal LTP by Ab [74]. Furthermore, GSK3 inhibitors are also reported to rescue LTP in a murine model of AD [78]. Thus, it is feasible that activation of PI 3-kinase and subsequent inhibition of GSK3b play a key role in leptin-dependent reversal of Ab inhibition of LTP.…”

Section: Leptin and Synaptic Function In Alzheimer's Diseasementioning

confidence: 99%

Leptin regulation of hippocampal synaptic function in health and disease

Irving

Harvey

2014

Phil. Trans. R. Soc. B

104

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The endocrine hormone leptin plays a key role in regulating food intake and body weight via its actions in the hypothalamus. However, leptin receptors are highly expressed in many extra-hypothalamic brain regions and evidence is growing that leptin influences many central processes including cognition. Indeed, recent studies indicate that leptin is a potential cognitive enhancer as it markedly facilitates the cellular events underlying hippocampal-dependent learning and memory, including effects on glutamate receptor trafficking, neuronal morphology and activity-dependent synaptic plasticity. However, the ability of leptin to regulate hippocampal synaptic function markedly declines with age and aberrant leptin function has been linked to neurodegenerative disorders such as Alzheimer's disease (AD). Here, we review the evidence supporting a cognitive enhancing role for the hormone leptin and discuss the therapeutic potential of using leptin-based agents to treat AD.

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Section: Leptin and Synaptic Function In Alzheimer's Diseasementioning

confidence: 99%

Leptin regulation of hippocampal synaptic function in health and disease

Irving

Harvey

2014

Phil. Trans. R. Soc. B

104

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“…Studies using analogues for the gut hormone glucagon-like peptide-1 (GLP-1) such as liraglutide, which facilitate insulin release, have shown that even short-term treatment can improve learning and memory, in addition to improving glucose homeostasis in mice with diet-induced obesity [7]. Moreover, an increase of GLP-1 signalling in the brain has also been suggested as a promising strategy to ameliorate the degenerative processes observed in Alzheimer's disease [8], while studies crossing APP mice to mouse models with alterations in brain insulin-signalling have revealed an important role for insulin signalling and glucose homeostasis in cognitive behaviour in these mice [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Susceptibility to diet-induced obesity and glucose intolerance in the APP SWE/PSEN1 A246E mouse model of Alzheimer’s disease is associated with increased brain levels of protein tyrosine phosphatase 1B (PTP1B) and retinol-binding protein 4 (RBP4), and basal phosphorylation of S6 ribosomal protein

et al. 2011

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Aims/hypothesis Obesity is a major risk factor for development of insulin resistance, a proximal cause of type 2 diabetes and is also associated with an increased relative risk of Alzheimer's disease. We therefore investigated the susceptibility of transgenic mice carrying human mutated transgenes for amyloid precursor protein (APP SWE ) and presenilin 1 (PSEN1 A246E ) (APP/PSEN1), or PSEN1 A246E alone, which are well-characterised animal models of Alzheimer's disease, to develop obesity, glucose intolerance and insulin resistance, and whether this was age-and/or diet-dependent. Methods We analysed the effects of age and/or diet on body weight of wild-type, PSEN1 and APP/PSEN1 mice. We also analysed the effects of diet on glucose homeostasis and insulin signalling in these mice. Results While there were no body weight differences between 16-17-and 20-21-month-old PSEN1 mice, APP/PSEN1 mice and their wild-type controls on standard, low-fat, chow diet, the APP/PSEN1 mice still exhibited impaired glucose homeostasis, as investigated by glucose tolerance tests. This was associated with increased brain protein tyrosine phosphatase 1B protein levels in APP/PSEN1 mice. Interestingly, short-term high-fat diet (HFD) feeding of wild-type, PSEN1and APP/PSEN1 mice for a period of 8 weeks led to higher body weight gain in APP/PSEN1 than in PSEN1 mice and wild-type controls. In addition, HFD-feeding caused fasting hyperglycaemia and worsening of glucose maintenance in PSEN1 mice, the former being further exacerbated in APP/ PSEN1 mice. The mechanism(s) behind this glucose intolerance in PSEN1 and APP/PSEN1 mice appeared to involve increased levels of brain retinol-binding protein 4 and basal phosphorylation of S6 ribosomal protein, and decreased insulin-stimulated phosphorylation of Akt/protein kinase B and extracellular signal-regulated kinase 1/2 in the brain. Conclusions/interpretation Our results indicate that Alzheimer's disease increases susceptibility to body weight gain induced by HFD, and to the associated glucose intolerance and insulin resistance.

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“…These authors identified quinostatin as a novel mTOR inhibitor through a high-throughput and cell-based assay [47]. The mTOR signalling pathway is relevant to various human diseases, including AD [48]. In vitro studies showed that Ab was an activator of the PI3K/AKT pathway, which in turn activated mTOR [49].…”

Section: Biological Insights Into Small Moleculementioning

confidence: 99%

Constructing and characterizing a bioactive small molecule and microRNA association network for Alzheimer's disease

Meng

Dai

et al. 2014

J. R. Soc. Interface.

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Alzheimer's disease (AD) is an incurable neurodegenerative disorder. Much effort has been devoted to developing effective therapeutic agents. Recently, targeting microRNAs (miRNAs) with small molecules has become a novel therapy for human diseases. In this study, we present a systematic computational approach to construct a bioactive Small molecule and miRNA association Network in AD (SmiRN-AD), which is based on the gene expression signatures of bioactive small molecule perturbation and AD-related miRNA regulation. We also performed topological and functional analysis of the SmiRN-AD from multiple perspectives. At the significance level of p ≤ 0.01, 496 small molecule–miRNA associations, including 25 AD-related miRNAs and 275 small molecules, were recognized and used to construct the SmiRN-AD. The drugs that were connected with the same miRNA tended to share common drug targets ( p = 1.72 × 10 −4 ) and belong to the same therapeutic category ( p = 4.22 × 10 −8 ). The miRNAs that were linked to the same small molecule regulated more common miRNA targets ( p = 6.07 × 10 −3 ). Further analysis of the positive connections (quinostatin and miR-148b, amantadine and miR-15a) and the negative connections (melatonin and miR-30e-5p) indicated that our large-scale predictions afforded specific biological insights into AD pathogenesis and therapy. This study proposes a holistic strategy for deciphering the associations between small molecules and miRNAs in AD, which may be helpful for developing a novel effective miRNA-associated therapeutic strategy for AD. A comprehensive database for the SmiRN-AD and the differential expression patterns of the miRNA targets in AD is freely available at http://bioinfo.hrbmu.edu.cn/SmiRN-AD/ .

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Dysregulation of the mTOR Pathway Mediates Impairment of Synaptic Plasticity in a Mouse Model of Alzheimer's Disease

Cited by 219 publications

References 48 publications

Leptin regulation of hippocampal synaptic function in health and disease

Leptin regulation of hippocampal synaptic function in health and disease

Susceptibility to diet-induced obesity and glucose intolerance in the APP SWE/PSEN1 A246E mouse model of Alzheimer’s disease is associated with increased brain levels of protein tyrosine phosphatase 1B (PTP1B) and retinol-binding protein 4 (RBP4), and basal phosphorylation of S6 ribosomal protein

Constructing and characterizing a bioactive small molecule and microRNA association network for Alzheimer's disease

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