mTOR Signaling in Epileptogenesis: Too Much of a Good Thing?

Cao, Ruifeng; Li, Aiqing; Cho, Hee Yeon

doi:10.1523/jneurosci.3486-09.2009

Cited by 19 publications

(10 citation statements)

References 12 publications

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“…Nevertheless, consistent with our data showing that reduction of mTOR signaling in non-Tg mice has no effect on learning and memory, it has been shown that rapamycin at low concentrations has no effects on different behavioral tests in wild type mice while reducing mTOR signaling (10,11). It is tempting to speculate that there may be a window of mTOR signaling that is optimal for learning and memory and alterations that would lead to an increase or decrease in mTOR signaling outside such an optimal window may have detrimental effects on learning and memory (61)(62)(63).…”

Section: Discussionmentioning

confidence: 99%

Molecular Interplay between Mammalian Target of Rapamycin (mTOR), Amyloid-β, and Tau

Caccamo

Majumder

Richardson

et al. 2010

Journal of Biological Chemistry

783

637

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Accumulation of amyloid-␤ (A␤) and Tau is an invariant feature of Alzheimer disease (AD). The upstream role of A␤ accumulation in the disease pathogenesis is widely accepted, and there is strong evidence showing that A␤ accumulation causes cognitive impairments. However, the molecular mechanisms linking A␤ to cognitive decline remain to be elucidated. Here we show that the buildup of A␤ increases the mammalian target of rapamycin (mTOR) signaling, whereas decreasing mTOR signaling reduces A␤ levels, thereby highlighting an interrelation between mTOR signaling and A␤. The mTOR pathway plays a central role in controlling protein homeostasis and hence, neuronal functions; indeed mTOR signaling regulates different forms of learning and memory. Using an animal model of AD, we show that pharmacologically restoring mTOR signaling with rapamycin rescues cognitive deficits and ameliorates A␤ and Tau pathology by increasing autophagy. Indeed, we further show that autophagy induction is necessary for the rapamycinmediated reduction in A␤ levels. The results presented here provide a molecular basis for the A␤-induced cognitive deficits and, moreover, show that rapamycin, an FDA approved drug, improves learning and memory and reduces A␤ and Tau pathology. Neurofibrillary tangles (NFTs)2 and amyloid plaques represent the two major hallmark neuropathological lesions of AD (1). NFTs are intraneuronal inclusions that are mainly formed of the hyperphosphorylated microtubule-binding protein Tau (2-5). In contrast, amyloid plaques accumulate extracellularly and are mainly composed of a peptide called amyloid-␤ (A␤) (6, 7). Although the key role of A␤ accumulation in the pathogenesis of AD is widely accepted, the molecular pathways by which A␤ accumulation leads to cognitive decline and Tau pathology remain to be elucidated.The mammalian target of rapamycin (mTOR) is a conserved Ser/Thr kinase that forms two multiprotein complexes known as mTOR complex (mTORC) 1 and 2 (8). mTORC1 controls cellular homeostasis, and its activity is inhibited by rapamycin; in contrast mTORC2 is insensitive to rapamycin and controls cellular shape by modulating actin function (8, 9). By regulating both protein synthesis and degradation, mTOR plays a key role in controlling protein homeostasis and hence brain function; indeed, mTOR activity has been directly linked to learning and memory (10 -13). Additionally, genetic and pharmacological reduction of mTOR activity has been shown to increase the lifespan in different organisms including yeast, Drosophila, and mice (14 -19).mTOR is an inhibitor of macroautophagy, which is a conserved intracellular system designed for the degradation of long-lived proteins and organelles in lysosomes (20 -22). Cumulative evidence suggests that an age-dependent decrease in the autophagy/lysosome system may account for the accumulation of abnormal proteins during aging (23). Macroautophagy (herein referred to as autophagy) is induced when an isolation membrane is generated surrounding cytosolic components, forming an autopha...

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Section: Discussionmentioning

confidence: 99%

Molecular Interplay between Mammalian Target of Rapamycin (mTOR), Amyloid-β, and Tau

Caccamo

Majumder

Richardson

et al. 2010

Journal of Biological Chemistry

783

637

View full text Add to dashboard Cite

show abstract

“…Although numerous downstream mechanisms may mediate epileptogenesis, less is known about initial signaling pathways that trigger the subsequent changes in the brain causing epilepsy. The mammalian target of rapamycin (mTOR), a conserved serine/threonine protein kinase, is crucial for many forms of synaptic plasticity in the adult brain (Cao et al, 2009). Studies have revealed that mTOR activity is up-regulated or down-regulated in brain tumors, tuberous sclerosis complex, cortical dysplasia, traumatic brain injury, and several neurodegenerative disorders (Inoki et al, 2005;Hoeffer and Klann, 2010).…”

Section: Novel Approaches For Antiepileptogenesis In Post-status Epilmentioning

confidence: 99%

Prevention or Modification of Epileptogenesis after Brain Insults: Experimental Approaches and Translational Research

Löscher¹,

Brandt²

2010

Pharmacol Rev

365

366

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“…Notably, low doses of rapamycin rescued the memory deficits associated with cannabinoids consumption (55). Overall, it appears that there may be a window for mTOR signaling that is optimal for learning and memory and that alterations leading to an excessive increase or decrease in mTOR signaling outside such optimal window may have detrimental effects on learning and memory (62-64). …”

Section: Mtor In Learning and Memorymentioning

confidence: 99%

The role of mTOR signaling in Alzheimer disease

Oddo¹

2012

Front Biosci

212

160

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The buildup of Abeta and tau is believed to directly cause or contribute to the progressive cognitive deficits characteristic of Alzheimer disease. However, the molecular pathways linking Abeta and tau accumulation to learning and memory deficits remain elusive. There is growing evidence that soluble forms of Abeta and tau can obstruct learning and memory by interfering with several signaling cascades. In this review, I will present data showing that the mammalian target of rapamycin (mTOR) may play a role in Abeta and tau induced neurodegeneration.

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mTOR Signaling in Epileptogenesis: Too Much of a Good Thing?

Cited by 19 publications

References 12 publications

Molecular Interplay between Mammalian Target of Rapamycin (mTOR), Amyloid-β, and Tau

Molecular Interplay between Mammalian Target of Rapamycin (mTOR), Amyloid-β, and Tau

Prevention or Modification of Epileptogenesis after Brain Insults: Experimental Approaches and Translational Research

The role of mTOR signaling in Alzheimer disease

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