Genetically augmenting tau levels does not modulate the onset or progression of Aβ pathology in transgenic mice

Oddo, Salvatore; Caccamo, Antonella; Cheng, David; Jouleh, Bahareh; Torp, Reidun; LaFerla, Frank M.

doi:10.1111/j.1471-4159.2007.04607.x

Cited by 73 publications

(66 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Tau pathology (e.g. somatodendritic Tau accumulation and hyperphosphorylation) starts to become apparent at this age, although to a smaller degree than intraneuronal A␤ (45,48). Intraneuronal A␤ accumulation and Tau pathology are both significantly higher at 12 months of age when compared with 6-month-old mice (45).…”

Section: Resultsmentioning

confidence: 87%

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

Self Cite

161

132

View full text Add to dashboard Cite

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...

show abstract

Section: Resultsmentioning

confidence: 87%

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

Self Cite

161

132

View full text Add to dashboard Cite

show abstract

“…2xTg (tau and APP mutant) or 3xTg (tau, APP and PS mutant) mice exhibit enhanced neurofibrillary tangle formation [47][48][49][50], which was attributed to activation of glycogen synthase kinase (GSK)-3β and Cdk5 [49,51], and inhibited proteasome activity [50]. Additional overexpression of tau does not enhance Aβ pathology in vivo [51], supporting the notion that tau pathology is downstream of Aβ. The effects on tau seen in the 2xTg mouse can be recapitulated by direct Aβ fibril injection, implying that Aβ is the minimal fragment of APP required to transform tau [52].…”

Section: Challenges In Targeting Amyloidmentioning

confidence: 82%

“…Aβ-induced tau hyperphosphorylation consequently caused microtubule disassembly [41,43], reduction of total soluble tau and an increase in tau fragments [44], missorting of tau into dendritic areas [41], activation of the nuclear transcription factor of activated T cells' apoptotic pathways [45,46], and cell toxicity [41,44]. 2xTg (tau and APP mutant) or 3xTg (tau, APP and PS mutant) mice exhibit enhanced neurofibrillary tangle formation [47][48][49][50], which was attributed to activation of glycogen synthase kinase (GSK)-3β and Cdk5 [49,51], and inhibited proteasome activity [50]. Additional overexpression of tau does not enhance Aβ pathology in vivo [51], supporting the notion that tau pathology is downstream of Aβ.…”

Section: Challenges In Targeting Amyloidmentioning

confidence: 99%

Biometals and Their Therapeutic Implications in Alzheimer's Disease

2015

View full text Add to dashboard Cite

No disease modifying therapy exists for Alzheimer's disease (AD). The growing burden of this disease to our society necessitates continued investment in drug development. Over the last decade, multiple phase 3 clinical trials testing drugs that were designed to target established disease mechanisms of AD have all failed to benefit patients. There is, therefore, a need for new treatment strategies. Changes to the transition metals, zinc, copper, and iron, in AD impact on the molecular mechanisms of disease, and targeting these metals might be an alternative approach to treat the disease. Here we review how metals feature in molecular mechanisms of AD, and we describe preclinical and clinical data that demonstrate the potential for metal-based drug therapy.

show abstract

“…Several evidences suggest that the link between Aβ and tau is predominantly, if not exclusively, unidirectional. In fact, tau has no effect on the onset and progression of Aβ accumulation (35). Rather, tau accumulation occurs after amyloid plaques formation, further exacerbating the neurotoxicity induced by Aβ.…”

Section: R E S E a R C H A R T I C L Ementioning

confidence: 99%

Apoptosis in Transgenic Mice Expressing the P301L Mutated Form of Human Tau

Ramalho

Viana

Castro

et al. 2008

Mol Med

View full text Add to dashboard Cite

The rTg4510 mouse is a tauopathy model, characterized by massive neurodegeneration in Alzheimer's disease (AD)-relevant cortical and limbic structures, deficits in spatial reference memory, and progression of neurofibrillary tangles (NFT). In this study, we examined the role of apoptosis in neuronal loss and associated tau pathology. The results showed that DNA fragmentation and caspase-3 activation are common in the hippocampus and frontal cortex of young rTg4510 mice. These changes were associated with cleavage of tau into smaller intermediate fragments, which persist with age. Interestingly, active caspase-3 was often co-localized with cleaved tau. In vitro, fibrillar Aβ 1-42 resulted in nuclear fragmentation, caspase activation, and caspase-3-induced cleavage of tau. Notably, incubation with the antiapoptotic molecule tauroursodeoxycholic acid abrogated apoptosis-mediated cleavage of tau in rat cortical neurons. In conclusion, caspase-3-cleaved intermediate tau species occurred early in rTg54510 brains and preceded cell loss in Aβ-exposed cultured neurons. These results suggest a potential role of apoptosis in neurodegeneration.

show abstract

Genetically augmenting tau levels does not modulate the onset or progression of Aβ pathology in transgenic mice

Cited by 73 publications

References 29 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

Biometals and Their Therapeutic Implications in Alzheimer's Disease

Apoptosis in Transgenic Mice Expressing the P301L Mutated Form of Human Tau

Contact Info

Product

Resources

About