High sensitivity to carcinogens in the brain of a mouse model of Alzheimer's disease

Serrano, Julia; Fernández, Ana Patricia; Martı́nez-Murillo, Ricardo; Martı́nez, Alfredo

doi:10.1038/onc.2009.503

Cited by 28 publications

(22 citation statements)

References 53 publications

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“…Zhou and Jia [50] demonstrated a p53-mediated G1/S checkpoint dysfunction in lymphocytes from sporadic AD, due to p53 conformational changes that affected its tertiary structure. Furthermore, Serrano et al, [51] demonstrated a significant increase of unfolded p53 in older AD transgenic mice when compared with younger APPswe/PS1A246E animals and wild-type counterparts of the same age. These latter data suggest also a correlation between unfolded p53 and aging.…”

Section: Discussionmentioning

confidence: 96%

Conformational Altered p53 as an Early Marker of Oxidative Stress in Alzheimer's Disease

et al. 2012

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In order to study oxidative stress in peripheral cells of Alzheimer's disease (AD) patients, immortalized lymphocytes derived from two peculiar cohorts of patients, referring to early onset AD (EOSAD) and subjects harboured AD related mutation (ADmut), were used. Oxidative stress was evaluated measuring i) the typical oxidative markers, such as HNE Michel adducts, 3 Nitro-Tyrosine residues and protein carbonyl on protein extracts, ii) and the antioxidant capacity, following the enzymatic kinetic of superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GRD). We found that the signs of oxidative stress, measured as oxidative marker levels, were evident only in ADmut but not in EOSAD patients. However, oxidative imbalance in EOSAD as well as ADmut lymphocytes was underlined by a reduced SOD activity and GRD activity in both pathological groups in comparison with cells derived from healthy subjects. Furthermore, a redox modulated p53 protein was found conformational altered in both EOSAD and ADmut B lymphocytes in comparison with control cells. This conformational altered p53 isoform, named “unfolded p53”, was recognized by the use of two specific conformational anti-p53 antibodies. Immunoprecipitation experiments, performed with the monoclonal antibodies PAb1620 (that recognizes p53wt) and PAb240 (that is direct towards unfolded p53), and followed by the immunoblotting with anti-4-hydroxynonenal (HNE) and anti- 3-nitrotyrosine (3NT) antibodies, showed a preferential increase of nitrated tyrosine residues in unfolded p53 isoform comparing to p53 wt protein, in both ADmut and EOSAD. In addition, a correlation between unfolded p53 and SOD activity was further found. Thus this study suggests that ROS/RNS contributed to change of p53 tertiary structure and that unfolded p53 can be considered as an early marker of oxidative imbalance in these patients.

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Section: Discussionmentioning

confidence: 96%

Conformational Altered p53 as an Early Marker of Oxidative Stress in Alzheimer's Disease

et al. 2012

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“…However, current evidence seems to point to the existence of direct co-morbidities between brain tumors and CNS diseases 16, 47, 48 . Additionally, a mouse model of AD displays high sensitivity to brain tumors 49 . We propose here that the significant number of genes deregulated in the same direction in both diseases could be an additional argument in favor of direct co-morbidity between AD and GBM.…”

Section: Discussionmentioning

confidence: 99%

A molecular hypothesis to explain direct and inverse co-morbidities between Alzheimer’s Disease, Glioblastoma and Lung cancer

Sánchez-Valle

Tejero

Ibáñez

et al. 2017

Sci Rep

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Epidemiological studies indicate that patients suffering from Alzheimer’s disease have a lower risk of developing lung cancer, and suggest a higher risk of developing glioblastoma. Here we explore the molecular scenarios that might underlie direct and inverse co-morbidities between these diseases. Transcriptomic meta-analyses reveal significant numbers of genes with inverse patterns of expression in Alzheimer’s disease and lung cancer, and with similar patterns of expression in Alzheimer’s disease and glioblastoma. These observations support the existence of molecular substrates that could at least partially account for these direct and inverse co-morbidity relationships. A functional analysis of the sets of deregulated genes points to the immune system, up-regulated in both Alzheimer’s disease and glioblastoma, as a potential link between these two diseases. Mitochondrial metabolism is regulated oppositely in Alzheimer’s disease and lung cancer, indicating that it may be involved in the inverse co-morbidity between these diseases. Finally, oxidative phosphorylation is a good candidate to play a dual role by decreasing or increasing the risk of lung cancer and glioblastoma in Alzheimer’s disease.

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“…Such a functional relationship between APP expression and proliferation demonstrates the importance of APP in the pathogenesis of cancer. APP-overexpressing mice are prone to develop brain carcinomas (43). However, the precise mechanism underlying the tumor growth-promoting effect of APP remains to be clarified.…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase Inhibitor Valproic Acid Inhibits Cancer Cell Proliferation via Down-regulation of the Alzheimer Amyloid Precursor Protein

Venkataramani

Roßner

Iffland

et al. 2010

Journal of Biological Chemistry

111

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The ␤-amyloid precursor protein (APP) represents a type I transmembrane glycoprotein that is ubiquitously expressed. In the brain, it is a key player in the molecular pathogenesis of Alzheimer disease. Its physiological function is however less well understood. Previous studies showed that APP is up-regulated in prostate, colon, pancreatic tumor, and oral squamous cell carcinoma. In this study, we show that APP has an essential role in growth control of pancreatic and colon cancer. Abundant APP staining was found in human pancreatic adenocarcinoma and colon cancer tissue. Interestingly, treating pancreatic and colon cancer cells with valproic acid (VPA, 2-propylpentanoic acid), a known histone deacetylase (HDAC) inhibitor, leads to up-regulation of GRP78, an endoplasmic reticulum chaperone immunoglobulin-binding protein. GRP78 is involved in APP maturation and inhibition of tumor cell growth by down-regulation of APP and secreted soluble APP␣. Trichostatin A, a pan-HDAC inhibitor, also lowered APP and increased GRP78 levels. In contrast, treating cells with valpromide, a VPA derivative lacking HDAC inhibitory properties, had no effect on APP levels. VPA did not modify the level of epidermal growth factor receptor, another type I transmembrane protein, and APLP2, a member of the APP family, demonstrating the specificity of the VPA effect on APP. Small interfering RNA-mediated knockdown of APP also resulted in significantly decreased cell growth. Based on these observations, the data suggest that APP downregulation via HDAC inhibition provides a novel mechanism for pancreatic and colon cancer therapy. ␤-Amyloid precursor protein (APP)2 is a highly conserved single transmembrane protein (type I) with a receptor-like structure and consists of a heterogeneous group of proteins migrating between 110 and 135 kDa (1, 2). The heterogeneity is due to alternative splicing, leading to eight distinct isoforms (namely APP677, APP695, APP696, APP714, APP733, APP751, APP752, and APP770), as well as by a variety of post-translational modifications, including O-and N-glycosylation, sulfation, and phosphorylation. APP isoforms exist as immature (N-glycosylated) and mature (N-and O-glycosylated, tyrosylsulfated) species. Immature APP localizes in the endoplasmic reticulum and cis-Golgi, and the mature APP form preferentially localizes in the trans-Golgi network, secretory and endocytic vesicles, and at the plasma membrane (3, 4).APP695 is the most common isoform in the central nervous system, whereas APP751 and APP770 are predominantly expressed in non-neuronal cells (5). The key event in the pathogenic cascade in Alzheimer disease is the amyloidogenic pathway characterized by subsequent cleavage of APP by the enzyme ␤-secretase and further processing by ␥-secretase, which finally leads to the generation of A␤ peptides. However, the predominant route of APP processing consists of successive cleavages by ␣-and ␥-secretases in non-neuronal cells (6, 7). The cleavage of APP at Lys 16 -Leu 17 bond by ␣-secretase within the A␤ sequence ...

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High sensitivity to carcinogens in the brain of a mouse model of Alzheimer's disease

Cited by 28 publications

References 53 publications

Conformational Altered p53 as an Early Marker of Oxidative Stress in Alzheimer's Disease

Conformational Altered p53 as an Early Marker of Oxidative Stress in Alzheimer's Disease

A molecular hypothesis to explain direct and inverse co-morbidities between Alzheimer’s Disease, Glioblastoma and Lung cancer

Histone Deacetylase Inhibitor Valproic Acid Inhibits Cancer Cell Proliferation via Down-regulation of the Alzheimer Amyloid Precursor Protein

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