Integrated copy number and gene expression analysis detects a CREB1 association with Alzheimer’s disease

Li, Y.; Shaw, Chad A.; Sheffer, Irene; Süle, Norbert; Powell, Suzanne Zein-Eldin; Dawson, Brian; Zaidi, Sameer; Bucasas, Kristine L.; Lupski, James R.; Wilhelmsen, K. C.; Doody, Rachelle S.; Szigeti, Kinga

doi:10.1038/tp.2012.119

Cited by 17 publications

(14 citation statements)

References 39 publications

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“…A previous study demonstrated that subjects with spatial memory impairment had lower hippocampal levels of CREB1 (Brightwell et al, 2004 ). CREB is a member of the family of leucine-zipper transcription factors, while CREB1 has been reported to promote cell signal transduction (Li et al, 2012 ). What’s more, the phosphorylation of CREB1 has been highlighted due to its involvement in the synthesis of an array of proteins, of which play significant roles in neuronal functions, including that of protein kinase A (PKA) (Murphy Jr et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: Effects of CREB1 gene silencing on cognitive dysfunction by mediating PKA-CREB signaling pathway in mice with vascular dementia

Han

Wen

Wang

et al. 2018

Mol Med

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BackgroundAs a form of dementia primarily affecting the elderly, vascular dementia (VD) is characterized by changes in the supply of blood to the brain, resulting in cognitive impairment. The aim of the present study was to explore the effects involved with cyclic adenosine monophosphate (cAMP) response element-binding (CREB)1 gene silencing on cognitive dysfunction through meditation of the protein kinase A (PKA)-CREB signaling pathway in mice with VD.MethodsBoth the Morris water maze test and the step down test were applied to assess the cognitive function of the mice with VD. Immunohistochemical and TUNEL staining techniques were employed to evaluate the positive expression rates of the protein CREB1 and Cleaved Caspase-3, as well as neuronal apoptosis among hippocampal tissues in a respective manner. Flow cytometry was applied to determine the proliferation index and apoptosis rate of the hippocampal cells among each group. Reverse transcription quantitative polymerase chain reaction and Western blot analysis methods were applied to detect the expressions of cAMP, PKA and CREB in hippocampal cells.ResultsCompared with the normal group, all the other groups exhibited impaired cognitive function, reduced cell numbers in the CAI area, positive expressions of CREB1 as well as positive optical density (OD) values. Furthermore, increased Cleaved Caspase-3 positive expression, OD value, proliferation index, apoptosis rate of hippocampal cells and neurons, were observed in the other groups when compared with the normal group, as well as lower expressions of cAMP, PKA and CREB1 and p-CREB1 (the shCREB1–1, H89 and shCREB1–1 + H89 groups < the VD group).ConclusionThe key findings of the present study demonstrated that CREB1 gene silencing results in aggravated VD that occurs as a result of inhibiting the PKA-CREB signaling pathway, thus exasperating cognitive dysfunction.

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Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: Effects of CREB1 gene silencing on cognitive dysfunction by mediating PKA-CREB signaling pathway in mice with vascular dementia

Han

Wen

Wang

et al. 2018

Mol Med

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“…Predicting the development and prognosis of AD is difficult, however, because only a small percentage of cases present with an autosomal dominant transmission pattern and an early disease onset that make genetic testing practical. To date, three causal genes have been identified which together account for less than 2% of AD: amyloid-beta protein precursor (APP) gene on chromosome 21 (Goate et al, 1991), presenilin1 (PSEN1) gene on chromosome 14 (Sherrington et al, 1995), and presenilin 2 (PSEN2) gene on chromosome 1 (Levy-Lahad et al, 1995; Sherrington et al, 1995) (Li et al, 2012). It has been suggested that a DNA diagnosis is attainable in about 70% of families with autosomal dominant AD and a clinical approach to genetic testing is well described (Liddell et al, 2001).…”

Section: Alzheimer's Diseasementioning

confidence: 99%

A review of quality of life after predictive testing for and earlier identification of neurodegenerative diseases

Paulsen¹,

Nance²,

Kim³

et al. 2013

Progress in Neurobiology

142

108

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The past decade has witnessed an explosion of evidence suggesting that many neurodegenerative diseases can be detected years, if not decades, earlier than previously thought. To date, these scientific advances have not provoked any parallel translational or clinical improvements. There is an urgency to capitalize on this momentum so earlier detection of disease can be more readily translated into improved health-related quality of life for families at risk for, or suffering with, neurodegenerative diseases. In this review, we discuss health-related quality of life (HRQOL) measurement in neurodegenerative diseases and the importance of these “patient reported outcomes” for all clinical research. Next, we address HRQOL following early identification or predictive genetic testing in some neurodegenerative diseases: Huntington disease, Alzheimer's disease, Parkinson's disease, Dementia with Lewy bodies, frontotemporal dementia, amyotrophic lateral sclerosis, prion diseases, hereditary ataxias, Dentatorubral-pallidoluysian atrophy and Wilson's disease. After a brief report of available direct-to-consumer genetic tests, we address the juxtaposition of earlier disease identification with assumed reluctance towards predictive genetic testing. Forty-one studies examining health related outcomes following predictive genetic testing for neurodegenerative disease suggested that (a) extreme or catastrophic outcomes are rare; (b) consequences commonly include transiently increased anxiety and/or depression; (c) most participants report no regret; (d) many persons report extensive benefits to receiving genetic information; and (e) stigmatization and discrimination for genetic diseases are poorly understood and policy and laws are needed. Caution is appropriate for earlier identification of neurodegenerative diseases but findings suggest further progress is safe, feasible and likely to advance clinical care.

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“…LINC00550 is of unknown function; however, it is overexpressed in neurofibrillary tangles as compared to neurons in subjects with AD (GEO: GDS2795). The chr2: 208,35 deletion upstream from CREB1 has been reported previously from the same dataset using alternative statistical approach incorporating gene expression as a quantitative trait and CNV into the model [24]. The chr15: 30,44 region was reported to be associated with AD [23].…”

Section: Discussionmentioning

confidence: 88%

Ordered Subset Analysis of Copy Number Variation Association with Age at Onset of Alzheimer's Disease

Szigeti

Kellermayer

Lentini

et al. 2014

JAD

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Genetic heterogeneity is a common problem for genome-wide association studies of complex human diseases. Ordered-subset analysis (OSA) reduces genetic heterogeneity and optimizes the use of phenotypic information, thus improving power under some disease models. We hypothesized that in a genetically heterogeneous disorder such as Alzheimer’s disease (AD), utilizing OSA by age at onset (AAO) of AD may increase the power to detect relevant loci. Using this approach, 8 loci were detected, including the chr15: 30,44 region harboring CHRFAM7A. The association was replicated in the NIA-LOAD Familial Study dataset. CHRFAM7A is a dominant negative regulator of CHRNA7 function, the receptor that facilitates amyloid-β1–42 internalization through endocytosis and has been implicated in AD. OSA, using AAO as a quantitative trait, optimized power and detected replicable signals suggesting that AD is genetically heterogeneous between AAO subsets.

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Integrated copy number and gene expression analysis detects a CREB1 association with Alzheimer’s disease

Cited by 17 publications

References 39 publications

RETRACTED ARTICLE: Effects of CREB1 gene silencing on cognitive dysfunction by mediating PKA-CREB signaling pathway in mice with vascular dementia

RETRACTED ARTICLE: Effects of CREB1 gene silencing on cognitive dysfunction by mediating PKA-CREB signaling pathway in mice with vascular dementia

A review of quality of life after predictive testing for and earlier identification of neurodegenerative diseases

Ordered Subset Analysis of Copy Number Variation Association with Age at Onset of Alzheimer's Disease

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