Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer's disease

Oddo, Salvatore; Caccamo, Antonella; Kitazawa, Masashi; Tseng, Bertrand P.; LaFerla, Frank M.

doi:10.1016/j.neurobiolaging.2003.08.012

Cited by 858 publications

(768 citation statements)

References 12 publications

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“…This occurred despite greater amounts of soluble Aβ1−40 and similar numbers of Aβ immunoreactive neurons in females. Because the available data suggest a causal role for early Aβ accumulation in the subsequent tau pathology in AD patients (Hardy and Allsop, 1991;Cummings, 2003;Mattson, 2004) and 3xTgAD mice (Oddo et al, 2003b;, our findings suggest the neurons in females may be more resistant to Aβ toxicity and associated tau pathology compared to neurons in male mice. The basis for this increased resistance of neurons in females to amyloid pathology is not known.…”

Section: Discussionmentioning

confidence: 70%

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Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice

Nelson

Guo

Halagappa

et al. 2007

Experimental Neurology

163

133

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A history of depression is a risk factor for Alzheimer's disease (AD), suggesting the possibility that antidepressants administered prophylactically might retard the disease process and preserve cognitive function. Here we report that pre-symptomatic treatment with the antidepressant paroxetine attenuates the disease process and improves cognitive performance in the 3xTgAD mouse model of AD. Five month-old male and female 3xTgAD and non-transgenic mice were administered either paroxetine or saline daily for 5 months. Open-field activity was tested in 7 month-old mice and performance in passive avoidance and Morris swim tasks were evaluated at 10 months. 3xTgAD mice exhibited reduced exploratory activity, increased transfer latency in the passive avoidance test and impaired performance in the Morris spatial navigation task compared to nontransgenic control mice. Paroxetine treatment ameliorated the spatial navigation deficit in 3xTgAD male and female mice, without affecting swim speed or distance traveled, suggesting a preservation of cognitive function. Levels of amyloid beta-peptide (Aβ) and numbers of Aβ immunoreactive neurons were significantly reduced in the hippocampus of male and female paroxetine-treated 3xTgAD mice compared to saline-treated 3xTgAD mice. Female 3xTgAD mice exhibited significantly less tau pathology in the hippocampus and amygdala compared to male 3xTgAD mice, and paroxetine lessened tau pathology in male 3xTgAD mice. The ability of a safe and effective antidepressant to suppress neuropathological changes and improve cognitive performance in a mouse model, suggests that such drugs administered prophylactically might retard the development of AD in humans.

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Section: Discussionmentioning

confidence: 70%

“…3D). Plaque-like deposits of Aβ were not observed at this middle stage of disease progression in the 3xTgAD mice (see Oddo et al, 2003b). No Aβ immunoreactivity was observed in brain sections from non-transgenic mice (data not shown).…”

Section: Amyloid β-Peptide Pathology Is Reduced In Paroxetine-treatedmentioning

confidence: 83%

Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice

Nelson

Guo

Halagappa

et al. 2007

Experimental Neurology

163

133

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“…Levels of oxidative damage in CNS tissue have not yet been reported for a P301 tau transgenic mouse that develops NFTs primarily in spinal cord [71], nor for a model of P301 tau conditional expression that develops NFTs in forebrain [72]. A transgenic mouse expressing mutant APP, PS1, and tau recently has been developed as a more "complete" model of AD pathologic changes, developing both Aβ plaques and NFTs [73,74]. However, we are unaware of any study of this strain that has examined the role of oxidative damage.…”

Section: Transgenic Micementioning

confidence: 99%

Free radical-mediated damage to brain in Alzheimer's disease and its transgenic mouse models

Sonnen¹,

Breitner²,

Lovell³

et al. 2008

Free Radical Biology and Medicine

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“…These so-called 3xTg-AD mice bear both the Swedish (KM670/671NL) APP mutation and the PS1 (M146V) mutation leading to overproduction and deposition of Aβ as well as the human four-repeat tau (P301L) mutation leading to overproduction and deposition of tau [32,33]. Billings and coworkers [34] have summarized the neuropathological aspects of these mice that are reminiscent of AD: (1) Aβ plaques and neurofibrillary pathology develop in a hierarchical manner in AD-relevant brain regions, mainly the hippocampus, cortex, and amygdala; (2) Aβ plaque pathology precedes tangle formation, and plaques consist of the longer, more amyloidogenic Aβ42; (3) the pattern of conformational and phosphorylation changes that the tau protein undergoes parallels the sequence in the human AD brain; and (4) the 3xTg-AD mice show selective loss of nicotinic α7 receptors in the hippocampus and cortex.…”

Section: Potential Uses Of An Aβ Imaging Agentmentioning

confidence: 99%

Impact of amyloid imaging on drug development in Alzheimer's disease

Mathis

Lopresti

Klunk

2007

Nuclear Medicine and Biology

111

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Imaging agents capable of assessing amyloid-beta (Aβ) content in vivo in the brains of Alzheimer's disease (AD) subjects likely will be important as diagnostic agents to detect Aβ plaques in the brain, to help test the amyloid cascade hypothesis of AD, and as an aid to assess the efficacy of anti-amyloid therapeutics currently under development and in clinical trials. Positron emission tomography (PET) imaging studies of amyloid deposition in human subjects with several Aβ imaging agents are currently underway. We reported the first PET studies of the carbon-11-labeled thioflavin-T derivative Pittsburgh Compound B ([ 11 C]PiB) in 2004, and this work has subsequently been extended to include a variety of subject groups including AD, mild cognitive impairment (MCI), and healthy controls. The ability to quantify regional Aβ plaque load in the brains of living human subjects has provided a means to begin to apply this technology as a diagnostic agent to detect regional concentrations of Aβ plaques and as a surrogate marker of therapeutic efficacy in anti-amyloid drug trials.

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Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer's disease

Cited by 858 publications

References 12 publications

Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice

Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice

Free radical-mediated damage to brain in Alzheimer's disease and its transgenic mouse models

Impact of amyloid imaging on drug development in Alzheimer's disease

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