Downregulation of extracellular signal-regulated kinase 1/2 activity by calmodulin KII modulates p21Cip1 levels and survival of immortalized lymphocytes from Alzheimer’s disease patients

Esteras, Noemí; Alquézar, Carolina; Bermejo‐Pareja, Félix; Białopiotrowicz, Emilia; Wojda, Urszula; Martín-Requero, Ángeles

doi:10.1016/j.neurobiolaging.2012.10.014

Cited by 23 publications

(19 citation statements)

References 67 publications

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“…In SAD lymphocytes an impaired progression of the G1/S phase occurs, consistent with p21's main change and its known function in arresting G1 [17]. Experiments with serum withdrawal also exhibited elevation of p21 level in the cytosol and changes of E2F and NF-κB transcription factors' activity [56]. The reduced NF-κB activation in AD cells seems to protect them from death induced by the loss of trophic factors.…”

Section: Dysregulated Cell Cycle In Lymphocytessupporting

confidence: 63%

Search for Alzheimer's Disease Biomarkers in Blood Cells: Hypotheses-Driven Approach

et al. 2017

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Current Alzheimer's disease (AD) diagnostics is based on cognitive testing, and detecting amyloid Aβ and τ pathology by brain imaging and assays of cerebrospinal fluid. However, biomarkers identifying complex pathways contributing to pathology are lacking, especially for early AD. Preferably, such biomarkers should be more cost-effective and present in easily available diagnostic tissues, such as blood. Here, we summarize the recent findings of potential early AD molecular diagnostic biomarkers in blood platelets, lymphocytes and erythrocytes. We review molecular alterations which refer to such main hypotheses of AD pathogenesis as amyloid cascade, oxidative and mitochondrial stress, inflammation and alterations in cell cycle regulatory molecules. The major advantage of such biomarkers is the potential ability to indicate individualized therapies in AD patients. Alzheimer's disease (AD) is the most prevalent age-related dementia worldwide and one of the major unmet, increasing medical and economic problems of the modern world. As of 2015, there were an estimated 46.8 million people with dementia worldwide. This number will increase to an estimated 74.7 million in 2030 [1].Among the neuropathological hallmarks of AD are: the progressive loss of brain neurons, synaptic degeneration and the deposition of extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs) in such regions of the brain as the hippocampus, cortex and amygdala. Amyloid plaques consist mainly of 40-and 42-amino-acid Aβ peptides (Aβ40 and Aβ42). Peptides are proteolytic cleavage products of the Aβ protein precursor (APP) but with no fully elucidated biological function. NFTs are deposits of paired helical filaments composed mainly of hyperphosphorylated τ protein, a microtubule-stabilizing protein that maintains neuronal cell structure and axonal transport. Nevertheless, neither senile plaques nor NFTs are absolute hallmarks of AD dementia, because cognitively intact aged individuals may exhibit both pathological changes upon postmortem brain examination or as assessed by positron emission tomography amyloid and τ imaging agents (amyloid-PET and τ-PET) [2][3][4][5].Clinical AD manifests by aggravating dysfunction and weakening functional cognitive processes, linked to brain neuron loss that is both progressive and permanent [4], and that within several years leads to total dependence on the caregiver and eventually to death. Advances in our knowledge of AD have shown that clinical symptoms usually develop after a long preclinical pathogenic process, lasting for decades, making early AD detection in asymptomatic patients a subject of great interest [4,5]. Increasing proof demonstrates that the therapeutic methods' effectiveness is strictly contingent on the early diagnosis of AD, before the occurrence of massive neuron loss and dementia. This highlights the key importance of biochemical biomarkers for early AD diagnostics. AD diagnostics & demand for novel, improved biomarkersThe broadly accepted recommendations for AD diagnosis...

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Section: Dysregulated Cell Cycle In Lymphocytessupporting

confidence: 63%

Search for Alzheimer's Disease Biomarkers in Blood Cells: Hypotheses-Driven Approach

et al. 2017

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“…In contrast, significant downregulation of MDM2 has also been observed in some diseases. For example, MDM2 expression is downregulated in AD, AKI, DN, and DCM . All of these changes in the expression of MDM2 may be considered as a potential biomarker for the diagnosis of these diseases.…”

Section: General Discussion and Future Research Directionsmentioning

confidence: 99%

“…Recent studies have indicated that MDM2 also contributes to the pathogenesis of AD via p53‐independent mechanisms (Figure ). Esteras et al have shown that MDM2 is downregulated in the lymphoblasts from AD patients compared with control lymphoblasts. MDM2 downregulation in AD may lead to FOXO3a stabilization, which in turn increases p21 transcription and promotes the pathogenesis of AD …”

Section: Roles Of Mdm2 In Dementia and Neurodegenerative Diseasesmentioning

confidence: 99%

Targeting MDM2 for novel molecular therapy: Beyond oncology

Wang

Qin

Rajaei

et al. 2019

Medicinal Research Reviews

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The murine double minute 2 (MDM2) oncogene exerts major oncogenic activities in human cancers; it is not only the bestdocumented negative regulator of the p53 tumor suppressor, but also exerts p53-independent activities. There is an increasing interest in developing MDM2-based targeted therapies. Several classes of MDM2 inhibitors have been evaluated in preclinical models, with a few entering clinical trials, mainly for cancer therapy. However, noncarcinogenic roles for MDM2 have also been identified, demonstrating that MDM2 is involved in many chronic diseases and conditions such as inflammation and autoimmune diseases,

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“…The higher CaM content was associated with impaired cell survival/death mechanisms [15,36]. Since cell cycle dysfunction seems to be a convergent point in neurodegenerative diseases [37], it was interesting to determine whether the control failure of CaM levels was commonly involved in neurodegenerative processes or, otherwise, was a disease-specific marker.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, the CaM content appears to regulate the rate of p27 degradation in AD cells through a phosphoinositide-3 kinase/Akt-dependent mechanism [15]. Moreover, higher levels of CaM also correlated with the resistance of AD cells to serum deprivation-induced apoptosis [36]. CaM thus seems to play a pivotal role in transmitting proliferative/survival signals from the plasma membrane to the nucleus.…”

Section: Discussionmentioning

confidence: 99%

Calmodulin levels in blood cells as a potential biomarker of Alzheimer’s disease

Esteras

Alquézar

Encarnación

et al. 2013

Alzheimers Res Ther

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IntroductionThe clinical features of Alzheimer’s disease (AD) overlap with a number of other dementias and conclusive diagnosis is only achieved at autopsy. Accurate in-life diagnosis requires finding biomarkers suitable for early diagnosis, as well as for discrimination from other types of dementia. Mounting evidence suggests that AD-dependent processes may also affect peripheral cells. We previously reported that calmodulin (CaM) signaling is impaired in AD lymphoblasts. Here, we address the issue as to whether the assessment of CaM levels in peripheral cells could serve as a diagnostic biomarker.MethodsA total of 165 subjects were enrolled in the study, including 56 AD patients, 15 patients with mild cognitive impairment, 7 with frontotemporal dementia associated with progranulin mutations, 4 with dementia with Lewy bodies, 20 patients with Parkinson’s disease, 10 with amyotrophic lateral sclerosis, 5 with progressive supranuclear palsy, and 48 cognitively normal individuals. CaM levels were then analyzed in lymphoblasts, peripheral blood mononuclear cells and plasma. Receiver operating characteristic (ROC) curve analyses were employed to evaluate the diagnostic performance of CaM content in identifying AD patients.ResultsCompared with control individuals, CaM levels were significantly increased in AD cells, but not in the other neurodegenerative disorders. CaM levels differentiated AD from control with a sensitivity of 0.89 and a specificity of 0.82 and were not dependent on disease severity or age. MCI patients also showed higher levels of the protein.ConclusionsCaM levels could be considered a peripheral biomarker for AD in its early stage and help to discriminate from other types of dementia.

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Downregulation of extracellular signal-regulated kinase 1/2 activity by calmodulin KII modulates p21Cip1 levels and survival of immortalized lymphocytes from Alzheimer’s disease patients

Cited by 23 publications

References 67 publications

Search for Alzheimer's Disease Biomarkers in Blood Cells: Hypotheses-Driven Approach

Search for Alzheimer's Disease Biomarkers in Blood Cells: Hypotheses-Driven Approach

Targeting MDM2 for novel molecular therapy: Beyond oncology

Calmodulin levels in blood cells as a potential biomarker of Alzheimer’s disease

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