Decreased cortical FADD protein is associated with clinical dementia and cognitive decline in an elderly community sample

Ramos-Miguel, Alfredo; Garcı́a-Sevilla, Jesús A.; Barr, Alasdair M.; Bayer, Thomas A.; Falkai, Peter; Leurgans, Sue E.; Schneider, Julie A.; Bennett, David A.; Honer, William G.; García-Fuster, M. Julia

doi:10.1186/s13024-017-0168-x

Cited by 18 publications

(14 citation statements)

References 68 publications

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“…Additionally, this latter study also showed, in line with the present results, that while FADD was regulated in the hippocampus following repeated drug administration, p-FADD was not . Besides, a similar absence on p-FADD regulation was observed in an aged population in which a lower contents of FADD was associated with poorer cognitive performance (Ramos-Miguel et al, 2017), suggesting a more important role for total FADD form in cognition and ageing. Since FADD is decreased with ageing (Hernández-Hernández and García-Fuster, 2017) and in age-related neuropathologies (i.e.…”

Section: Discussionsupporting

confidence: 55%

“…Hernández-Hernández and García-Fuster, 2017) and in age-related neuropathologies (i.e. FADD as a putative biomarker of the cognitive decline associated with the course of clinical dementia; see Ramos-Miguel et al, 2017). In particular, this latter study demonstrated that cortical FADD protein was decreased in an elderly, community-based cohort of subjects with dementia, and that loss of FADD was associated among other things with poorer cognitive function and increased risk of dementia (Ramos-Miguel et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Repeated treatment with the α2-adrenoceptor agonist UK-14304 improves cognitive performance in middle-age rats: Role of hippocampal Fas-associated death domain

et al. 2017

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The cell fate regulator Fas-associated death domain (FADD) balances cell death with non-apoptotic actions via its phosphorylated form. A recent study associated loss of cortical FADD with cognitive decline and increased risk of clinical dementia. Since the activation of cortical α-adrenoceptors improved memory deficits in various animal models of working memory loss, the present study evaluated whether UK-14304, an α-adrenoceptor agonist known to acutely regulate brain FADD forms, would improve cognitive function in middle-aged rats. Sprague-Dawley rats were treated with UK-14304 (0.3 or 1 mg/kg) or saline (1 mL/kg) for seven days. Cognitive performance was evaluated in the eight-arm radial maze. FADD protein content was measured in the prefrontal cortex and hippocampus by Western blot analysis. The results showed that UK-14304 (1 mg/kg) improved cognitive performance (less time: -310±45 s, p=0.025 and fewer errors: -2.75±1.06, p=0.043 to complete the maze) and increased FADD selectively in the hippocampus (+35±11%, p=0.029). Interestingly, hippocampal FADD content negatively correlated with the time ( r=-0.651, p<0.01) needed to complete the maze. Thus, better cognitive scores were associated with higher FADD hippocampal content. These results support a role for α-adrenoceptors in ameliorating cognition and suggest FADD protein content as a possible correlate for cognitive performance.

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Section: Discussionsupporting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Repeated treatment with the α2-adrenoceptor agonist UK-14304 improves cognitive performance in middle-age rats: Role of hippocampal Fas-associated death domain

et al. 2017

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“…Disrupted FADD phosphorylation has been inversely correlated with tumor aggressiveness in T-cell lymphoblastic lymphomas [98]. Moreover, decreased FADD is associated with cognitive impairment and clinical dementia in the elderly [99]. In addition, a recent review has explored the roles of FADD in the context of cancer and inflammation, highlighting the impact of translational and post-translational modifications in its multiple functions [34].…”

Section: Extrinsic Pathwaymentioning

confidence: 99%

A Cell’s Fate: An Overview of the Molecular Biology and Genetics of Apoptosis

Cavalcante

Schaan

Cabral

et al. 2019

IJMS

162

112

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Apoptosis is one of the main types of regulated cell death, a complex process that can be triggered by external or internal stimuli, which activate the extrinsic or the intrinsic pathway, respectively. Among various factors involved in apoptosis, several genes and their interactive networks are crucial regulators of the outcomes of each apoptotic phase. Furthermore, mitochondria are key players in determining the way by which cells will react to internal stress stimuli, thus being the main contributor of the intrinsic pathway, in addition to providing energy for the whole process. Other factors that have been reported as important players of this intricate molecular network are miRNAs, which regulate the genes involved in the apoptotic process. Imbalance in any of these mechanisms can lead to the development of several illnesses, hence, an overall understanding of these processes is essential for the comprehension of such situations. Although apoptosis has been widely studied, the current literature lacks an updated and more general overview on this subject. Therefore, here, we review and discuss the mechanisms of apoptosis, highlighting the roles of genes, miRNAs, and mitochondria involved in this type of cell death.

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“…In the literature, an association of FADD increase with poor clinical outcome has been described in many solid tumors [4,5,6,7,8,9,10,18,109,150,151,152]. In contrast, a reduction of FADD has been reported in fewer tumor types, among them hematological malignancies [11,12,13,14,15], but also in pathologies different from cancer like dementia [153]. Altered levels of phosphorylated FADD have also been reported, either a reduction [12,13,154,155,156] or an increase [5,7,37,98,100,101,102], but in all cases associated with poor outcome.…”

Section: Clinical Implications Of Fadd Alterations In Cancermentioning

confidence: 99%

FADD in Cancer: Mechanisms of Altered Expression and Function, and Clinical Implications

Marín-Rubio

Vela‐Martín

Fernández‐Piqueras

et al. 2019

Cancers

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FADD was initially described as an adaptor molecule for death receptor-mediated apoptosis, but subsequently it has been implicated in nonapoptotic cellular processes such as proliferation and cell cycle control. During the last decade, FADD has been shown to play a pivotal role in most of the signalosome complexes, such as the necroptosome and the inflammasome. Interestingly, various mechanisms involved in regulating FADD functions have been identified, essentially posttranslational modifications and secretion. All these aspects have been thoroughly addressed in previous reviews. However, FADD implication in cancer is complex, due to pleiotropic effects. It has been reported either as anti- or protumorigenic, depending on the cell type. Regulation of FADD expression in cancer is a complex issue since both overexpression and downregulation have been reported, but the mechanisms underlying such alterations have not been fully unveiled. Posttranslational modifications also constitute a relevant mechanism controlling FADD levels and functions in tumor cells. In this review, we aim to provide detailed, updated information on alterations leading to changes in FADD expression and function in cancer. The participation of FADD in various biological processes is recapitulated, with a mention of interesting novel functions recently proposed for FADD, such as regulation of gene expression and control of metabolic pathways. Finally, we gather all the available evidence regarding the clinical implications of FADD alterations in cancer, especially as it has been proposed as a potential biomarker with prognostic value.

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Decreased cortical FADD protein is associated with clinical dementia and cognitive decline in an elderly community sample

Cited by 18 publications

References 68 publications

Repeated treatment with the α2-adrenoceptor agonist UK-14304 improves cognitive performance in middle-age rats: Role of hippocampal Fas-associated death domain

Repeated treatment with the α2-adrenoceptor agonist UK-14304 improves cognitive performance in middle-age rats: Role of hippocampal Fas-associated death domain

A Cell’s Fate: An Overview of the Molecular Biology and Genetics of Apoptosis

FADD in Cancer: Mechanisms of Altered Expression and Function, and Clinical Implications

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