Presenilin 1 gene silencing by <i>S</i>‐adenosylmethionine: a treatment for Alzheimer disease?

Scarpa, Sigfrido; Fuso, Andrea; D’Anselmi, Fabrizio; Cavallaro, Rosaria A.

doi:10.1016/s0014-5793(03)00277-1

Cited by 185 publications

(116 citation statements)

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“…Additionally, treatment of peripheral blood mononuclear cells isolated from AD patients with an acetylcholinesterase inhibitor, a compound that has shown some degree of effectiveness in slowing down the progression of AD, resulted in a decrease in IL-1␤ production (22). The regulation of methylation, specifically of promoters, has been implicated in the onset and progression of AD (27,28); however, there is nothing in the literature examining the histone acetylation status in AD patients at present.…”

Section: Resultsmentioning

confidence: 99%

Molecular inhibition of histone deacetylation results in major enhancement of the production of IL-1β in response to LPS

Sato¹,

Mitchell²

2006

American Journal of Physiology-Endocrinology and Metabolism

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It has been postulated that the progression of human pregnancy to term is, in part, the result of a relative maternal Th 2 immunological state. This can be activated in some cell types by modifying DNA methylation and histone acetylation status. We demonstrate that the molecular inhibition of histone deacetylation, using trichostatin A (TSA), in human choriodecidual explants leads to a massive increase in lipopolysaccharide (LPS)-stimulated IL-1␤. The inhibition of histone deacetylation had no effect on LPS-stimulated TNF-␣ production or production of the other cytokines studied (IL-10, IL-1 receptor antagonist). The molecular inhibition of DNA methylation and histone deacetylation, using 5-aza-2Ј-deoxycytidine and TSA, respectively, in human choriodecidual explants also results in an increase in the basal production of TNF-␣ but not that of IL-1␤. The differential response is unique, and the relative uncoupling of IL-1␤ and TNF-␣ responsiveness may have importance in other biological systems and provide new therapeutic targets for pathologies where upregulation of IL-1␤ is known to be a causative factor. interleukin-1␤; lipopolysaccharide; histane deacetylation; human pregnancy CYTOKINES ARE KEY INFLAMMATORY MEDIATORS that regulate numerous cellular responses (20). They can be categorized as proinflammatory (e.g., IL-1␤ and TNF-␣) or anti-inflammatory [e.g., IL-10 and IL-1 receptor antagonist (IL-1Ra)] depending on the cellular response initiated. Cytokines can further be categorized as Th 1 or Th 2 on the basis of whether they initiate a cellular or antibody-generating immune response, respectively (18). Maintenance of a Th 2 type phenotype is critical to the maintenance of pregnancy (11,17,34). Recent studies have demonstrated that alterations of DNA methylation in T cells can lead to an adaption to a Th 2 type phenotype (14).Prostaglandin H synthase (PGHS)-2 is a key biosynthetic enzyme of arachidonic acid metabolism. Recent reports have demonstrated that PGHS-2 activity is suppressed in cancer cell lines by aberrantly enhanced DNA methylation and reduced histone acetylation; activity can be restored by treatment with inhibitors of DNA methylation and histone deacetylation (12,32). Enhanced intrauterine prostaglandin production is requisite for the onset and progression of labor at term and preterm, and the most extremely preterm deliveries are mainly a result of an intrauterine infection associated with increased cytokine production (24). Recently, we (16) have demonstrated that prostaglandin production by intrauterine tissues of women at term of pregnancy can be regulated by inhibition of DNA methylation and histone deacetylation. Hence, we hypothesize that the regulation of DNA methylation and histone acetylation in key genes in human gestational tissues may be critical for the initiation of labor and delivery both at term and preterm.To evaluate this proposition, we have now determined the effects of inhibiting DNA methylation and histone deacetylation on cytokine production by human choriodecidua, which...

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Section: Resultsmentioning

confidence: 99%

Molecular inhibition of histone deacetylation results in major enhancement of the production of IL-1β in response to LPS

Sato¹,

Mitchell²

2006

American Journal of Physiology-Endocrinology and Metabolism

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“…Cell culture data support the possibility that tHcy may increase A␤ levels: Homocysteine enhances A␤ generation by upregulating a presenilin-interacting endoplasmic reticulum stress protein 43 ; deficient methylation upregulates presenilin gene function and A␤ generation. 44 Although the correlation of tHcy and A␤ was independent of diagnosis in this cross-sectional study, age-related correlated increases in tHcy and A␤ may contribute to neurotoxicity and AD risk. Homocysteine potentiates A␤ oxidative toxicity in cultured neurons and smooth muscle cells and in APP transgenic mice.…”

Section: Figure 2 Within Each Diagnostic Group Total Homocysteine (mentioning

confidence: 56%

Carotid dissection causing occipital lobe infarction

Cucchiara

Kasner

2005

Neurology

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Abstract-Background: Elevated plasma total homocysteine (tHcy) is a risk factor for cardiovascular disease and is reported to be an independent risk factor for Alzheimer disease (AD) and cognitive decline. tHcy may potentiate neurotoxic and vasculopathic processes, including amyloid ␤ protein (A␤) metabolism, implicated in neurodegenerative diseases. Objective: To examine the relationship of plasma total tHcy levels with clinical, demographic, biochemical, and genetic factors in aging, mild cognitive impairment (MCI), AD, cerebral amyloid angiopathy (CAA), and Parkinson disease (PD). Methods: Plasma tHcy, folate, vitamin B 12 , creatinine, and A␤ levels were assessed in individuals evaluated in the Memory, Stroke, and Movement Disorders Units of Massachusetts General Hospital with diagnoses of AD (n ϭ 145), MCI (n ϭ 47), PD (n ϭ 93), CAA (67), hypertensive intracerebral hemorrhage (hICH) (n ϭ 25), and no dementia (n ϭ 88). Results: The tHcy levels did not differ across AD, MCI, CAA, hICH, and nondemented control subjects but were increased in the PD group (p Ͻ 0.01). The elevated levels within the PD group were due to high tHcy in individuals taking levodopa (p Ͻ 0.0001). Increasing tHcy was associated with worse cognition in the PD cases, but not the other diagnostic groups. tHcy levels positively correlated with plasma A␤ levels even after adjustments for age and creatinine (p Ͻ 0.0001). Conclusions: Mean tHcy levels increased with age but did not discriminate diagnostic groups aside from significant elevation in patients with PD taking levodopa. The positive association between tHcy and plasma A␤ levels raises the possibility that these circulating factors could interact to affect AD risk and cognition in PD.

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“…Studies from our laboratory and others demonstrate that folate deficiency potentiates several AD genetic risk factors, including increasing homocysteine, which potentiates Aβ neurotoxicity [47][48][49][50]. The decline in S-adenosyl methionine (SAM) that accompanies folate deficiency fosters PS-1 overexpression, increases activity of β-and γ-secretases, increases levels of Aβ [51][52][53][54], and compromises glutathione usage, which in turn increases oxidative stress and potentiates the impact of deficiency in ApoE function [3,55].…”

Section: Nutritional Deficiency Potentiates the Impact Of Deficiency mentioning

confidence: 98%

Apolipoprotein E3 as a Risk Factor for Alzheimer's Disease Under Conditions of Nutritional Imbalance

Chan

Shea

2010

JAD

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Abstract. The presence of one or more copies of the E4 allele of apolipoprotein E (ApoE) is strongly associated with of Alzheimer's disease (AD). The impact of E4 on neurodegeneration is potentiated by dietary oxidative challenge. Our prior studies in transgenic mice demonstrate that, in the face of dietary oxidative challenge, E3 does not provide any further protection than E4 or lack of murine ApoE for aggression, oxidative damage, presenilin-1 expression, and γ-secretase activity, and provides only partial reduction in phospho-tau levels. Extrapolation of these findings to the human condition leads us to hypothesize that the E3 allele may not provide sufficient neuroprotection under conditions of dietary compromise and/or oxidative challenge. Epidemiological evidence is consistent with this possibility. The E3 allele is approximately half as effective compared to E2 at buffering the impact of a single E4 allele. In addition, the risk of AD increases linearly for the genotypes E2/2, E2/3, and E3/3. It has been proposed that that clinical manifestation of AD may in some cases require the convergence of 2 or more risk factors. We hypothesize that the combined impact of dietary oxidative stress and either the ApoE3 or E4 genotype represents one such condition.Keywords: Alzheimer's disease, apolipoprotein E, diet, nutritional deficiency, oxidative stresss APOE, OXIDATIVE DAMAGE, AND ALZHEIMER'S DISEASEA major risk factor for Alzheimer's disease (AD) is the presence of the E4 allele of apolipoprotein E (ApoE), which accounts for up to 50% of the cases of AD [1][2][3][4][5]. Considerable effort has been devoted to determining the nature and extent of risk imparted by ApoE4 and what might be done to lessen this risk [6]. Oxidative damage represents an early and perhaps pivotal factor contributing to age-related decline in cogni- * Correspondence to: Thomas B. Shea, Center for Cellular Neurobiology and Neurodegeneration Research, UMassLowell, Lowell, Massachusetts 01854, USA. Tel.: +1 978 934 2881; Fax: +1 978 934 3044; E-mail: Thomas Shea@uml.edu. tive performance including that associated with AD [7][8][9][10][11][12]. Oxidative damage and ApoE4 are inter-related, as the extent of brain oxidative damage in AD is correlated with the presence of E4 [13][14][15][16]. ApoE mediates transport and clearance of lipids, including those subjected to oxidative damage. In doing so, ApoE prevents a cascade of neuronal oxidative damage by quenching downstream products of lipid oxidation, preventing secondary glutamate excitotoxicity and sequestering oxidative metals such as iron [4,17,18,20]. However, ApoE4 is thought to be less effective at this latter function [21].While over 20 other genes are suspected of being related to AD [22], deficiency in ApoE function has a particularly far-reaching impact in that it not only impairs overall brain metabolism and may impair compensato-

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Presenilin 1 gene silencing by S‐adenosylmethionine: a treatment for Alzheimer disease?

Cited by 185 publications

References 29 publications

Molecular inhibition of histone deacetylation results in major enhancement of the production of IL-1β in response to LPS

Molecular inhibition of histone deacetylation results in major enhancement of the production of IL-1β in response to LPS

Carotid dissection causing occipital lobe infarction

Apolipoprotein E3 as a Risk Factor for Alzheimer's Disease Under Conditions of Nutritional Imbalance

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