Peroxisomal Proliferation Protects from β-Amyloid Neurodegeneration

Abstract

Alzheimer disease is a neurodegenerative process that leads to severe cognitive impairment as a consequence of selective death of neuronal populations. The molecular pathogenesis of Alzheimer disease involves the participation of the ␤-amyloid peptide (A␤) and oxidative stress. We report here that peroxisomal proliferation attenuated A␤-dependent toxicity in hippocampal neurons. Pretreatment with Wy-14.463 (Wy), a peroxisome proliferator, prevent the neuronal cell death and neuritic network loss induced by the A␤ peptide. Moreover, the hippocampal neurons treated with this compound, showed an increase in the number of peroxisomes, with a concomitant increase in catalase activity. Additionally, we evaluate the Wy protective effect on ␤-catenin levels, production of intracellular reactive oxygen species, cytoplasmic calcium uptake, and mitochondrial potential in hippocampal neurons exposed to H 2 O 2 and A␤ peptide. Results show that the peroxisomal proliferation prevents ␤-catenin degradation, reactive oxygen species production, cytoplasmic calcium increase, and changes in mitochondrial viability. Our data suggest, for the first time, a direct link between peroxisomal proliferation and neuroprotection from A␤-induced degenerative changes.Peroxisomes are subcellular organelles found in most animal cells that perform diverse metabolic functions, including detoxification of reactive oxygen species (ROS) 2 through their matrix enzyme catalase (1-3) and regulation of the oxidative balance and fatty acid oxidation (4 -6). Peroxisomes are present in the cell bodies, dendrites, and presynaptic axon terminals of neuronal cells (7,8) as well as in growing neurites (9). Tau overexpression inhibits kinesin-dependent transport of peroxisomes, neurofilaments, and Golgi-derived vesicles into neurites (10), and it has been suggested that a loss of peroxisomes apparently makes neurons more vulnerable to oxidative stress (10). Peroxisome proliferators (PPs) are a class of structurally dissimilar industrial and pharmaceutical chemicals that were originally identified as inducers of peroxisome proliferation in rat and mouse hepatocytes (11,12). Several PPs have shown to bind to peroxisome proliferator-activated receptors (PPARs), these include Wy-14.643 (Wy), which binds with great affinity to PPAR␣ and induces a strong activation of this receptor (11). 4-Phenyl butyric (4-PB) is a PP that, in contrast to other PPs, is able to induce human peroxisome proliferation (13); however, the mechanism of peroxisome proliferation remains to be elucidated. According to Liu et al. (14), 4-PB activates PPARs in astrocytes; nevertheless, they suggested that peroxisome proliferation may be independent of PPAR␣ activation.Alzheimer disease (AD) is characterized by a progressive neurodegeneration associated with extracellular deposits of amyloid ␤-peptide (A␤) in the form of senile plaques (15,16). A␤ peptide acquires neurotoxic properties when it forms homo-oligomeric species (17) or heterooligomeric species with molecules associated with mature ...

Rosiglitazone Treatment Prevents Mitochondrial Dysfunction in Mutant Huntingtin-expressing Cells

“…Images were quantified using Image-Pro Plus 6 software. Results in intensity units were expressed as average of fluorescence signal (F) minus background fluorescence (F 0 ) in every image (29,30).…”

“…Mitochondrial Potential Determination in Live CellsMitochondria membrane potential was determined using Mitotracker Red CM-H 2 XRos (MitoRed) or TMRM (22,28,30). Striatal cells were grown on poly-L-lysine-coated plates and cultured for 4 days.…”

“…The images were analyzed with LCS Leica confocal software and recorded as mean MitoRed or TMRM fluorescence signal per live cell. Estimation of fluorescence intensities were presented as the pseudoratio (⌬F/F o ), which was calculated using the following formula: ⌬F/F o ϭ (F Ϫ F base )/(F base Ϫ B), where F is the measured fluorescence intensity of the indicator, F base is the fluorescence intensity before the stimulation, and B is the background signal determined from the average of areas adjacent to the cells (22,28,30).…”

“…The fluorescence changes determined by Fluo-3 represent the cytoplasmic calcium changes (30,31), and Rhod-2 fluorescence indicate calcium changes in the mitochondria (32,33,34). To estimate Rhod-2 fluorescence pattern in live mitochondria, we used Mitotracker Green TM dye (MitoGreen) (33).…”

Pro12Ala polymorphism in PPAR-γ2 and dementia in Chinese nonagenarians/centenarians

“…Pathophysiology of dementia depends on a variety of interrelated factors, in which the genetic determinant must be prominent in the development of dementia in view of the heritability of cognitive function. Peroxisome proliferator-activated receptors gamma (PPAR-γ) gene, as a candidate gene, seems to attract particular interest in relation to dementia (Santos et al 2005).…”