Article

The -Secretase-Derived C-Terminal Fragment of APP, C99, But Not A , Is a Key Contributor to Early Intraneuronal Lesions in Triple-Transgenic Mouse Hippocampus

Université de Nice-Sophia-Antipolis, Institut de Pharmacologie Moléculaire et Cellulaire, CNRS UMR 7275, Team "Fondation pour la Recherche Médicale" and "Laboratoire d'Excellence Distalz," 06560 Sophia-Antipolis, France, Elan Pharmaceuticals, South San Francisco, California 94080, Cap Delta-Parc Euromédecine, CNRS UMR 3145, SysDiag, 34184 Montpellier, France, and Center for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5S3H2, Canada.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 11/2012; 32(46):16243-16255. DOI: 10.1523/JNEUROSCI.2775-12.2012
Source: PubMed

ABSTRACT Triple-transgenic mice (3xTgAD) overexpressing Swedish-mutated β-amyloid precursor protein (βAPP(swe)), P310L-Tau (Tau(P301L)), and physiological levels of M146V-presenilin-1 (PS1(M146V)) display extracellular amyloid-β peptides (Aβ) deposits and Tau tangles. More disputed is the observation that these mice accumulate intraneuronal Aβ that has been linked to synaptic dysfunction and cognitive deficits. Here, we provide immunohistological, genetic, and pharmacological evidences for early, age-dependent, and hippocampus-specific accumulation of the β-secretase-derived βAPP fragment C99 that is observed from 3 months of age and enhanced by pharmacological blockade of γ-secretase. Notably, intracellular Aβ is only detectable several months later and appears, as is the case of C99, in enlarged cathepsin B-positive structures, while extracellular Aβ deposits are detected ∼12 months of age and beyond. Early C99 production occurs mainly in the CA1/subicular interchange area of the hippocampus corresponding to the first region exhibiting plaques and tangles in old mice. Furthermore, the comparison of 3xTgAD mice with double-transgenic mice bearing the βAPP(swe) and Tau(P301L) mutations but expressing endogenous PS1 (2xTgAD) demonstrate that C99 accumulation is not accounted for by a loss of function triggered by PS1 mutation that would have prevented C99 secondary cleavage by γ-secretase. Together, our work identifies C99 as the earliest βAPP catabolite and main contributor to the intracellular βAPP-related immunoreactivity in 3xTgAD mice, suggesting its implication as an initiator of the neurodegenerative process and cognitive alterations taking place in this mouse model.

0 Followers
 · 
150 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Postmenopausal women may be more vulnerable to cognitive loss and Alzheimer's disease (AD) than premenopausal women because of their deficiency in estrogens, in addition to their usually older age. Aerobic physical exercise has been proposed as a therapeutic approach for maintaining health and well-being in postmenopausal women, and for improving brain health and plasticity in populations at high risk for AD. To study the neuroprotective mechanisms of physical exercise in a postmenopausal animal model, we submitted previously ovariectomized, six-month old non-transgenic and 3xTg-AD mice to three months of voluntary exercise in a running wheel. At nine months of age, we observed lower grip strength and some exacerbation of the behavioral and psychological symptoms of dementia (BPSD)-like involving active exploratory activities. A similar major cognitive impairment was observed of ovariectomized 3xTg-AD mice in comparison with sham-operated 3xTg-AD mice. A reduction of bodily fitness and lack of retention of memory were observed in the ovariectomized non-transgenic mice. Physical exercise protected against all deleterious behaviors and normalized learning and memory. It also protected against body frailty, as expected. Analyses of hippocampal key markers of antioxidant and neuroplasticity signaling pathways, showed that ovariectomy impairs the activation of CREB through physical exercise. Furthermore, molecular and behavioral correlates suggested a central role of BDNF in the neuroprotection mediated by physical exercise therapy against apathy and memory loss induced by ovariectomy and the AD-genotype.
    Psychoneuroendocrinology 07/2014; DOI:10.1016/j.psyneuen.2014.03.021 · 5.59 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The amyloid precursor protein (APP) and amyloid-β (Aβ) peptide play central roles in the pathology and etiology of Alzheimer's disease. Amyloid-induced impairments in neurogenesis have been investigated in several transgenic mouse models but the mechanism of action remains to be conclusively demonstrated. The changes in neurogenesis during this transition of increasing Aβ levels and plaque formation was investigated in the present study. We found that the proliferation of newborn cell in the dentate gyrus was enhanced prior to elevations in soluble Aβ production as well as amyloid deposition in 5 week-old TgCRND8 mice, which are well-established Alzheimer's disease models, compared to non-transgenic (Non-Tg) mice. The number of BrdU-positive cells remained higher in TgCRND8 vs Non-Tg mice for a period of 8 weeks. The numbers of BrdU/NeuN-positive cells were not significantly different in TgCRND8 compared to non-transgenic mice. A significant decrease in BrdU/GFAP but not in BrdU/S100β was found in Tg vs Non-Tg at 6 week-old age. In addition, a unique observation was made using isolated neuroprogenitor cells from TgCRND8 mice which were found to be less viable in culture and produced substantial amounts of secreted Aβ peptides. This suggests that the proliferation of neural progenitors in vivo may be modulated by high levels of APP expression and the resulting Aβ generated directly by the progenitor cells. These findings indicate that cell proliferation is increased prior to Aβ deposition and that cell viability is decreased in TgCRND8 mice over time.
    Neuroscience 12/2013; 261. DOI:10.1016/j.neuroscience.2013.12.021 · 3.33 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Clues to Alzheimer disease (AD) pathogenesis come from a variety of different sources including studies of clinical and neuropathological features, biomarkers, genomics and animal and cellular models. An important role for amyloid precursor protein (APP) and its processing has emerged and considerable interest has been directed at the hypothesis that Aβ peptides induce changes central to pathogenesis. Accordingly, molecules that reduce the levels of Aβ peptides have been discovered such as γ-secretase inhibitors (GSIs) and modulators (GSMs). GSIs and GSMs reduce Aβ levels through very different mechanisms. However, GSIs, but not GSMs, markedly increase the levels of APP CTFs that are increasingly viewed as disrupting neuronal function. Here, we evaluated the effects of GSIs and GSMs on a number of neuronal phenotypes possibly relevant to their use in treatment of AD. We report that GSI disrupted retrograde axonal trafficking of brain-derived neurotrophic factor (BDNF), suppressed BDNF-induced downstream signaling pathways and induced changes in the distribution within neuronal processes of mitochondria and synaptic vesicles. In contrast, treatment with a novel class of GSMs had no significant effect on these measures. Since knockdown of APP by specific siRNA prevented GSI-induced changes in BDNF axonal trafficking and signaling, we concluded that GSI effects on APP processing were responsible, at least in part, for BDNF trafficking and signaling deficits. Our findings argue that with respect to anti-amyloid treatments, even an APP-specific GSI may have deleterious effects and GSMs may serve as a better alternative.
    PLoS ONE 02/2015; 10(2):e0118379. DOI:10.1371/journal.pone.0118379 · 3.53 Impact Factor