Increased Expression of Cyclooxygenases and Peroxisome Proliferator-Activated Receptor-γ in Alzheimer's Disease Brains

Kitamura, Yoshihisa; Shimohama, Shun; Koike, Hideyasu; Kakimura, Jun-ichi; Matsuoka, Yasuji; Nomura, Yasuyuki; Gebicke‐Haerter, Peter J.; Taniguchi, Takashi

doi:10.1006/bbrc.1998.9981

Cited by 202 publications

(129 citation statements)

References 30 publications

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“…The results are highly relevant because the generation of PGE 2 results from the combined actions of COX activity and PGE 2 synthesis enzymes. Nonetheless, as our Western blot analysis confirmed up-regulation of mPGES-1 in AD cortical tissue, other studies have also shown a corresponding up-regulation of COX-2 [32,33]. In light of the functional coupling of COX-2 and mPGES-1 [34], COX-2 might colocalize with mPGES-1 in pyramidal neurons.…”

Section: Discussionsupporting

confidence: 82%

Elevated microsomal prostaglandin‐E synthase‐1 in Alzheimer's disease

Chaudhry

Zhuang

Crain

et al. 2007

Alzheimer's & Dementia

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Section: Discussionsupporting

confidence: 82%

Elevated microsomal prostaglandin‐E synthase‐1 in Alzheimer's disease

Chaudhry

Zhuang

Crain

et al. 2007

Alzheimer's & Dementia

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“…Moreover, PPAR gamma agonists induce beta-catenin inhibition [3,5], which represents a rationale to use it when the Wnt/beta-catenin pathway is upregulated such as in Parkinson's disease, multiple sclerosis, ALS, Huntington's disease and Friedreich's ataxia [8]. However, in AD, PPAR gamma levels (mRNA and protein) have been found to be elevated in brain tissues [59,60]. Although PPAR gamma expression is high in AD, PPAR gamma agonists have been used in AD humans and various AD animal models and have been shown to induce beneficial effects, partly due to their anti-inflammatory effects [61][62][63][64][65][66][67].…”

Section: Discussionmentioning

confidence: 99%

Amyotrophic Lateral Sclerosis: Role of the Canonical Wnt/Beta- Catenin Pathway and PPAR Gamma

Lecarpentier¹,

Vallée²

2016

Update on Amyotrophic Lateral Sclerosis

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Amyotrophic lateral sclerosis (ALS) is one of the most common adult-onset debilitating neurodegenerative diseases (NDs) which is characterized by a chronic progressive degeneration of upper and lower motor neurons, resulting in muscular atrophy, paralysis and ultimately death. It has been established that in ALS, the canonical Wnt/ beta-catenin pathway is upregulated. Peroxisome proliferator-activated receptor gamma (PPAR gamma) generally varies in opposite way compared with the Wnt/betacatenin signaling. Several studies carried out on ALS transgenic mice have shown the beneficial effects induced after treatment by PPAR agonists partly due to antiinflammatory effects induced by PPAR gamma. The coupling between the Wnt/betacatenin signaling and PPAR gamma has led to divide NDs into two classes: NDs in which the Wnt/beta-catenin pathway is upregulated whereas PPAR gamma is downregulated (ALS, Parkinson's disease, Huntington's disease and Friedreich's ataxia); and NDs in which the Wnt-beta-catenin pathway is downregulated while PPAR gamma is upregulated (Alzheimer's disease, bipolar disorder and schizophrenia).

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“…COX-1 is expressed constitutively, whereas expression of COX-2 is induced under inflammatory conditions and is responsible for the progression of inflammation (20 -22). The following evidences of the involvement of PGE 2 (and COX-2) in the progression of AD suggest that they are good targets for the development of AD drugs: (i) Elevated levels of PGE 2 and overexpression of COX-2 have been observed in the brains of AD patients (23)(24)(25); (ii) the extent of COX-2 expression correlates with the amount of A␤ and the degree of progression of AD pathogenesis (26); (iii) transgenic mice constitutively overexpressing COX-2 show aging-dependent neural apoptosis and memory dysfunction (27); (iv) prolonged use of nonsteroidal anti-inflammatory drugs, inhibitors of COX, delays the onset and reduces the risk of AD (28); (v) PGE 2 stimulates the production of reactive oxygen species in microglia cells, resulting in activation of ␤-secretase (29).…”

mentioning

confidence: 99%

Prostaglandin E2 Stimulates the Production of Amyloid-β Peptides through Internalization of the EP4 Receptor

Hoshino

Namba

Takehara

et al. 2009

Journal of Biological Chemistry

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Amyloid-␤ (A␤) peptides, generated by the proteolysis of ␤-amyloid precursor protein by ␤-and ␥-secretases, play an important role in the pathogenesis of Alzheimer disease. Inflammation is also important. We recently reported that prostaglandin E 2 (PGE 2 ), a strong inducer of inflammation, stimulates the production of A␤ through EP 2 and EP 4 receptors, and here we have examined the molecular mechanism. Activation of EP 2 and EP 4 receptors is coupled to an increase in cellular cAMP levels and activation of protein kinase A (PKA). We found that inhibitors of adenylate cyclase and PKA suppress EP 2 , but not EP 4 , receptor-mediated stimulation of the A␤ production. In contrast, inhibitors of endocytosis suppressed EP 4 , but not EP 2 , receptor-mediated stimulation. Activation of ␥-secretase was observed with the activation of EP 4 receptors but not EP 2 receptors. PGE 2 -dependent internalization of the EP 4 receptor was observed, and cells expressing a mutant EP 4 receptor lacking the internalization activity did not exhibit PGE 2 -stimulated production of A␤. A physical interaction between the EP 4 receptor and PS-1, a catalytic subunit of ␥-secretases, was revealed by immunoprecipitation assays. PGE 2 -induced internalization of PS-1 and co-localization of EP 4 , PS-1, and Rab7 (a marker of late endosomes and lysosomes) was observed. Co-localization of PS-1 and Rab7 was also observed in the brain of wild-type mice but not of EP 4 receptor null mice. These results suggest that PGE 2 -stimulated production of A␤ involves EP 4 receptor-mediated endocytosis of PS-1 followed by activation of the ␥-secretase, as well as EP 2 receptor-dependent activation of adenylate cyclase and PKA, both of which are important in the inflammation-mediated progression of Alzheimer disease. Alzheimer disease (AD)2 is the most common neurodegenerative disorder of the central nervous system and the leading cause of adult onset dementia. AD is characterized pathologically by the accumulation of tangles and senile plaques. Senile plaques are composed of the amyloid-␤ (A␤) peptides A␤40 and A␤42 (1, 2). To generate A␤, ␤-amyloid precursor protein (APP) is first cleaved by ␤-secretase and then by ␥-secretase. Cleavage of APP by ␣-secretase produces non-amyloidogenic peptides (3, 4). The ␥-secretase is an aspartyl protease complex composed of four core components, including presenilin (PS) 1 and PS2 (5). Early onset familial AD is linked to three genes, APP, PS1, and PS2 (5, 6), strongly suggesting that ␥-secretasedependent production of A␤ is a key factor in the pathogenesis of AD. Therefore, cellular factors that affect the ␥-secretase-dependent production of A␤ may be good targets for the development of drugs to prevent and treat AD.Both APP and PS-1 are transmembrane proteins, and their intracellular localization is controlled by secretory and endocytic pathways. These proteins are modified in the endoplasmic reticulum and trafficked to the cell surface through the transGolgi network (TGN). Then, they are internalized again and traf...

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Increased Expression of Cyclooxygenases and Peroxisome Proliferator-Activated Receptor-γ in Alzheimer's Disease Brains

Cited by 202 publications

References 30 publications

Elevated microsomal prostaglandin‐E synthase‐1 in Alzheimer's disease

Elevated microsomal prostaglandin‐E synthase‐1 in Alzheimer's disease

Amyotrophic Lateral Sclerosis: Role of the Canonical Wnt/Beta- Catenin Pathway and PPAR Gamma

Prostaglandin E2 Stimulates the Production of Amyloid-β Peptides through Internalization of the EP4 Receptor

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