Activation of Akt/PKB, increased phosphorylation of Akt substrates and loss and altered distribution of Akt and PTEN are features of Alzheimer's disease pathology

Griffin, Rebecca J.; Moloney, Aileen M.; Kelliher, Mary; Johnston, Janet; Ravid, Rivka; Dockery, Peter; O’Connor, Rosemary; O’Neill, Cora

doi:10.1111/j.1471-4159.2004.02949.x

Cited by 409 publications

(323 citation statements)

References 41 publications

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“…For example, PI3K/mTOR signaling regulates Tau phosphorylation (24), and mTOR activation enhances Tau-induced neurodegeneration in a Drosophila model of tauopathies (78). Further strengthening the mTOR/Tau link are the data resulting from investigations of AD brains showing that mTOR signaling is selectively increased in neurons predicted to develop neurofibrillary tangles and that such an increase correlates with Tau phosphorylation (25)(26)(27)(28). This evidence has led to the hypothesis that the chronic increase in mTOR function occurring during aging may facilitate the development of Tau pathology (27).…”

Section: Discussionmentioning

confidence: 97%

“…insulin/insulin-like growth factor, cell energy status, nutrients, and stress) via different signaling transduction pathways (11), some of which are modulated by A␤ (20 -24). Indeed, evidence from AD brains shows that mTOR signaling is selectively increased in neurons predicted to develop neurofibrillary tangles and that such an increase correlates with Tau phosphorylation (25)(26)(27)(28). This evidence has led to the hypothesis that the chronic increase in mTOR function occurring during aging may facilitate the development of Tau pathology (27).…”

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confidence: 99%

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Naturally Secreted Amyloid-β Increases Mammalian Target of Rapamycin (mTOR) Activity via a PRAS40-mediated Mechanism

Caccamo¹,

Maldonado²,

Majumder³

et al. 2011

Journal of Biological Chemistry

159

132

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Reducing the mammalian target of rapamycin (mTOR) activity increases lifespan and health span in a variety of organisms. Alterations in protein homeostasis and mTOR activity and signaling have been reported in several neurodegenerative disorders, including Alzheimer disease (AD); however, the causes of such deregulations remain elusive. Here, we show that mTOR activity and signaling are increased in cell lines stably transfected with mutant amyloid precursor protein (APP) and in brains of 3xTg-AD mice, an animal model of AD. In addition, we show that in the 3xTg-AD mice, mTOR activity can be reduced to wild type levels by genetically preventing A␤ accumulation. Similarly, intrahippocampal injections of an anti-A␤ antibody reduced A␤ levels and normalized mTOR activity, indicating that high A␤ levels are necessary for mTOR hyperactivity in 3xTg-AD mice. We also show that the intrahippocampal injection of naturally secreted A␤ is sufficient to increase mTOR signaling in the brains of wild type mice. The mechanism behind the A␤-induced mTOR hyperactivity is mediated by the proline-rich Akt substrate 40 (PRAS40) as we show that the activation of PRAS40 plays a key role in the A␤-induced mTOR hyperactivity. Taken together, our data show that A␤ accumulation, which has been suggested to be the culprit of AD pathogenesis, causes mTOR hyperactivity by regulating PRAS40 phosphorylation. These data further indicate that the mTOR pathway is one of the pathways by which A␤ exerts its toxicity and further support the idea that reducing mTOR signaling in AD may be a valid therapeutic approach.Amyloid plaques and neurofibrillary tangles are hallmark neuropathological lesions of Alzheimer disease (AD), 3 the most common form of neurodegenerative disorder (1). Neurofibrillary tangles are intracellular inclusions formed of hyperphosphorylated Tau (2-4). Plaques are extracellular inclusions mainly formed of a small peptide called amyloid-␤ (A␤) (5, 6). Clinically, AD is characterized by profound memory loss and cognitive dysfunction (7). Growing evidence is converging on soluble A␤ as a mediator of early cognitive decline in AD (8, 9). Although the molecular mechanisms underlying A␤-induced cognitive decline remain elusive, soluble A␤ oligomers have been shown to alter signal transduction pathways that are key for learning and memory, suggesting that alterations in such pathways may underlie the onset of cognitive decline in AD (10).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 (11). mTORC1 controls protein homeostasis; its activity is inhibited by rapamycin, and it contains mTOR, raptor, proline-rich Akt substrate 40 kDa (PRAS40), and mLT8. mTORC2, which is insensitive to rapamycin, controls cellular shape by modulating actin function and contains mTOR, rictor, mLST8, and hSIN (11, 12). In mTORC1, raptor binds to mTOR substrates and is necessary for mTOR activity (13). PRAS40 is another mTOR regulatory protein, which inhibits mTOR...

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Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 99%

Naturally Secreted Amyloid-β Increases Mammalian Target of Rapamycin (mTOR) Activity via a PRAS40-mediated Mechanism

Caccamo¹,

Maldonado²,

Majumder³

et al. 2011

Journal of Biological Chemistry

159

132

View full text Add to dashboard Cite

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“…Conflicting results, however, have been reported for the activity of this pathway in sporadic AD. Zunbenco et al (1999) reported reduced PI3K activity in AD brain tissue, whereas Griffin et al (2005) reported increased Akt phosphorylation in AD brain. Postmortem delays in the removal and processing of human brain tissue have been shown to affect both the stability and phosphorylation of many proteins (Ferrer et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Wild-Type But Not FAD Mutant Presenilin-1 Prevents Neuronal Degeneration by Promoting Phosphatidylinositol 3-Kinase Neuroprotective Signaling

Baki

Neve²,

Shao³

et al. 2008

J. Neurosci.

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The role of presenilin-1 (PS1) in neuronal phosphatidylinositol 3-kinase (PI3K)/Akt signaling was investigated in primary neuronal cultures from wild-type (WT) and PS1 null (PS1؊/؊) embryonic mouse brains. Here we show that in PS1Ϫ/Ϫ cultures, the onset of neuronal maturation coincides with a decrease in the PI3K-dependent phosphorylation-activation of Akt and phosphorylationinactivation of glycogen synthase kinase-3 (GSK-3). Mature PS1Ϫ/Ϫ neurons show increased activation of apoptotic caspase-3 and progressive degeneration preceded by dendritic retraction. Expression of exogenous WT PS1 or constitutively active Akt in PS1Ϫ/Ϫ neurons stimulates PI3K signaling and suppresses both caspase-3 activity and dendrite retraction. The survival effects of PS1 are sensitive to inhibitors of PI3K kinase but insensitive to ␥-secretase inhibitors. Familial Alzheimer disease (FAD) mutations suppress the ability of PS1 to promote PI3K/AKT signaling, prevent phosphorylation/inactivation of GSK-3 and promote activation of caspase-3. These mutation effects are reversed upon coexpression of constitutively active Akt. Together, our data indicate that the neuroprotective role of PS1 depends on its ability to activate the PI3K/Akt signaling pathway and that PS1 FAD mutations increase GSK-3 activity and promote neuronal apoptosis by inhibiting the function of PS1 in this pathway. These observations suggest that stimulation of PI3K/Akt signaling may be beneficial to FAD patients.

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“…Due to its ability to affect cell fate and activities by influencing survival and other central regulatory pathways, Akt has become a prominent point of focus in various fields of research ranging from tumorigenesis to diabetes and Alzheimer's disease (Testa and Bellacosa, 2001;Lu et al, 2003;Griffin et al, 2005;Robertson, 2005;Zdychova and Komers, 2005). In recent years, Akt has also been shown to impact microbial pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

“…T308 is phosphorylated by PI-dependent kinase (PDK) 1, and then at a second site, serine 473 (S473), located within the C-terminal regulatory domain of Akt by an as-yet unidentified kinase designated as PDK2 Stephens et al, 1998;Song et al, 2005). Phosphorylation of both T308 and S473 is required for full activation of Akt (Alessi et al, 1996).Due to its ability to affect cell fate and activities by influencing survival and other central regulatory pathways, Akt has become a prominent point of focus in various fields of research ranging from tumorigenesis to diabetes and Alzheimer's disease (Testa and Bellacosa, 2001;Lu et al, 2003;Griffin et al, 2005;Robertson, 2005;Zdychova and Komers, 2005). In recent years, Akt has also been shown to impact microbial pathogenesis.…”

mentioning

confidence: 99%

Inactivation of Host Akt/Protein Kinase B Signaling by Bacterial Pore-forming Toxins

Wiles

Dhakal

Eto

et al. 2008

MBoC

102

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Uropathogenic Escherichia coli (UPEC) are the major cause of urinary tract infections (UTIs), and they have the capacity to induce the death and exfoliation of target uroepithelial cells. This process can be facilitated by the pore-forming toxin ␣-hemolysin (HlyA), which is expressed and secreted by many UPEC isolates. Here, we demonstrate that HlyA can potently inhibit activation of Akt (protein kinase B), a key regulator of host cell survival, inflammatory responses, proliferation, and metabolism. HlyA ablates Akt activation via an extracellular calcium-dependent, potassium-independent process requiring HlyA insertion into the host plasma membrane and subsequent pore formation. Inhibitor studies indicate that Akt inactivation by HlyA involves aberrant stimulation of host protein phosphatases. We found that two other bacterial pore-forming toxins (aerolysin from Aeromonas species and ␣-toxin from Staphylococcus aureus) can also markedly attenuate Akt activation in a dose-dependent manner. These data suggest a novel mechanism by which sublytic concentrations of HlyA and other pore-forming toxins can modulate host cell survival and inflammatory pathways during the course of a bacterial infection. INTRODUCTIONStrains of uropathogenic Escherichia coli (UPEC) are the leading cause of urinary tract infections (UTIs), which currently rank among the most common of infectious diseases worldwide (Foxman, 2003;Marrs et al., 2005). During the course of an infection, UPEC can stimulate a number of antimicrobial, proinflammatory, prodifferentiation, proliferation, and host cell death pathways (Mulvey, 2002;Mysorekar et al., 2002). In some cases, UPEC can reportedly modulate these signaling events, causing attenuation of host inflammatory responses and potentiating host apoptotic cascades (Klumpp et al., 2001(Klumpp et al., , 2006Hunstad et al., 2005;Billips et al., 2007). These phenomena have been linked in part to the suppression of nuclear factor-B (NF B) activation and downstream signaling by unknown factors associated with UPEC (Klumpp et al., 2001;Hunstad et al., 2005). By hindering host cytokine expression and ensuing inflammatory responses, UPEC may be better able to establish itself and multiply within the cells and tissues of the urinary tract. At the same time, UPEC-induced death of bladder and renal epithelial cells can compromise mucosal barriers, and it may thereby facilitate bacterial dissemination and persistence within the urinary tract (Mulvey et al., 1998Chen et al., 2003a;Bower et al., 2005;Eto et al., 2006;Mansson et al., 2007b).A key regulator of host cell survival pathways is Akt (also known as protein kinase B, PKB; for recent reviews, see Fayard et al., 2005;Song et al., 2005;Manning and Cantley, 2007). This serine/threonine kinase is able to inhibit apoptosis, and it can help control cell cycle and metabolic pathways, endocytosis and vesicular trafficking, and host inflammatory responses, including the activation of NF B. Akt is activated downstream of phosphoinositide 3-kinase (PI3-kinase), which it...

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Activation of Akt/PKB, increased phosphorylation of Akt substrates and loss and altered distribution of Akt and PTEN are features of Alzheimer's disease pathology

Cited by 409 publications

References 41 publications

Naturally Secreted Amyloid-β Increases Mammalian Target of Rapamycin (mTOR) Activity via a PRAS40-mediated Mechanism

Naturally Secreted Amyloid-β Increases Mammalian Target of Rapamycin (mTOR) Activity via a PRAS40-mediated Mechanism

Wild-Type But Not FAD Mutant Presenilin-1 Prevents Neuronal Degeneration by Promoting Phosphatidylinositol 3-Kinase Neuroprotective Signaling

Inactivation of Host Akt/Protein Kinase B Signaling by Bacterial Pore-forming Toxins

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