Temporal Profile of Amyloid-β (Aβ) Oligomerization in an in Vivo Model of Alzheimer Disease

Oddo, Salvatore; Caccamo, Antonella; Tran, L.T.; Lambert, Mary P.; Glabe, Charles G.; Klein, William L.; LaFerla, Frank M.

doi:10.1074/jbc.m507892200

Cited by 363 publications

(285 citation statements)

References 41 publications

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“…As the 3xTg-AD mice age, they gradually accumulate A␤ and Tau pathology in their brains. Specifically, 6-month-old mice are characterized by intraneuronal accumulation of soluble A␤ (45,53). Tau pathology (e.g.…”

Section: Resultsmentioning

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

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161

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: Resultsmentioning

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

Self Cite

161

132

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“…The major histopathological features of AD brain include the accumulation of diffuse/ neuritic plaques composed of β-amyloid (Aβ) and the appearance of neurofibrillary tangles composed of phosphorylated tau [51]. Although the detailed interactions between Aβ and tau remain unknown, recent findings in triple transgenic mice harboring mutant APP, mutant presenilin 1 and mutant tau provided support for Aβ positively regulating tau pathology [52].…”

Section: Contribution Of Complex IV Defects To Oxidative Stress and Nmentioning

confidence: 99%

The mitochondrial impairment, oxidative stress and neurodegeneration connection: reality or just an attractive hypothesis?

Fukui

Moraes

2008

Trends in Neurosciences

221

146

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Aging is the most important risk factor for common neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. Aging in the central nervous system has been associated with elevated mutation load in mitochondrial DNA, defects in mitochondrial respiration and increased oxidative damage. These observations support a 'vicious cycle' theory which states that there is a feedback mechanism connecting these events in aging and age-associated neurodegeneration. Despite being an extremely attractive hypothesis, the bulk of the evidence supporting the mitochondrial vicious cycle model comes from pharmacological experiments in which the modes of mitochondrial enzyme inhibition are far from those observed in real life. Furthermore, recent in vivo evidence does not support this model. In this review, we focus on the relationship among the components of the putative vicious cycle, with particular emphasis on the role of mitochondrial defects on oxidative stress. Mitochondrial respiratory chain and reactive oxygen species productionMitochondria, being the key players in ATP production and diverse cell signaling events, are essential organelles for the survival of eukaryotic cells. Unlike all other organelles in animals, the mitochondria have their own genome (mitochondrial DNA; mtDNA) that encodes components of the oxidative phosphorylation (OXPHOS) system. The mitochondrial OXPHOS machinery is composed of five multisubunit complexes (complex I-V). From Krebs cycle intermediates (NADH and FADH 2 ), electrons feed into complex I or II, and are transferred to complex III, then to complex IV, and finally to O 2 . The redox energy released during the electron transfer process in complexes I, III and IV is utilized to actively pump out H + from the mitochondrial matrix to the intermembrane space, generating the electrochemical gradient of H + across the inner membrane which is ultimately utilized by complex V to produce ATP [1].This elegant system for energy production, however, is not perfect. A small portion (up to 2%) of electrons passing through the electron transport chain, mostly at complex I and complex III, react with molecular oxygen and yield superoxide anion, which can be converted into other reactive oxygen species (ROS) such as hydrogen peroxide and the highly reactive hydroxyl radical through enzymatic and nonenzymatic reactions [2]. Cells are endowed with robust endogenous antioxidant systems to counteract excessive ROS. It is believed that ROS, in particular hydrogen peroxide, have physiological roles as signaling molecules [3,4]. However,

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“…Recent experimental evidence in vitro and in vivo supports soluble Aβ oligomers as the predominant toxic species for neurons [76,77]. SAMP8 shows spontaneous overproduction of soluble Aβ in the hippocampus [26] and cortex [58].…”

Section: Histopathological Similarities In Samp8 and Admentioning

confidence: 99%

Senescence-Accelerated Mice P8: A Tool to Study Brain Aging and Alzheimer's Disease in a Mouse Model

Pallàs

2012

ISRN Cell Biology

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The causes of aging remain unknown, but they are probably intimately linked to a multifactorial process that affects cell networks to varying degrees. Although a growing number of aging and Alzheimer's disease (AD) animal models are available, a more comprehensive and physiological mouse model is required. In this context, the senescence-accelerated mouse prone 8 (SAMP8) has a number of advantages, since its rapid physiological senescence means that it has about half the normal lifespan of a rodent. In addition, according to data gathered over the last five years, some of its behavioral traits and histopathology resemble AD human dementia. SAMP8 has remarkable pathological similarities to AD and may prove to be an excellent model for acquiring more in-depth knowledge of the age-related neurodegenerative processes behind brain senescence and AD in particular. We review these facts and particularly the data on parameters related to neurodegeneration. SAMP8 also shows signs of aging in the immune, vascular, and metabolic systems, among others.

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Temporal Profile of Amyloid-β (Aβ) Oligomerization in an in Vivo Model of Alzheimer Disease

Cited by 363 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

The mitochondrial impairment, oxidative stress and neurodegeneration connection: reality or just an attractive hypothesis?

Senescence-Accelerated Mice P8: A Tool to Study Brain Aging and Alzheimer's Disease in a Mouse Model

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