Early and sustained altered expression of aging-related genes in young 3xTg-AD mice

Gatta, Valentina; D’Aurora, Marco; Granzotto, Alberto; Stuppia, Liborio; Sensi, Stefano L.

doi:10.1038/cddis.2014.11

Cited by 39 publications

(43 citation statements)

References 61 publications

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“…Previous studies have shown that the Egr-1 level is up-regulated in AD brains (18 -21, 37). Furthermore, levels of both BACE-1 and Egr-1 are elevated in the brain during aging (22,38,39), hypoxia, brain injury, ischemia, and inflammation (13,14) and in AD mouse models (13,21,23). These observations together indicate that Egr-1 is an activator of BACE-1 in the CNS and suggest that Egr-1 plays role in the up-regulation of levels of BACE-1 and A␤ in AD brain.…”

Section: Discussionmentioning

confidence: 50%

Early Growth Response 1 (Egr-1) Is a Transcriptional Activator of β-Secretase 1 (BACE-1) in the Brain

Qin

Wang

Paudel

2016

Journal of Biological Chemistry

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Accumulation of amyloid-␤ peptide (A␤) in the brain is regarded as central to Alzheimer's disease (AD) pathogenesis. A␤ is generated by a sequential cleavage of amyloid precursor protein (APP) by ␤-secretase 1 (BACE-1) followed by ␥-secretase. BACE-1 cleavage of APP is the committed step in A␤ synthesis. Understanding the mechanism by which BACE-1 is activated leading to A␤ synthesis in the brain can provide better understanding of AD pathology and help to develop novel therapies. In this study, we found that the levels of A␤ and BACE-1 are significantly reduced in the brains of mice lacking transcription factor early growth response 1 (Egr-1) when compared with the WT. We demonstrate that in COS-7 cells, Egr-1 binds to the BACE-1 promoter and activates BACE-1 transcription. In rat hippocampal primary neurons, overexpression of Egr-1 induces BACE-1 expression, activates BACE-1, promotes amyloidogenic APP processing, and enhances A␤ synthesis. In mouse hippocampal primary neurons, knockdown of BACE-1 almost completely blocks Egr-1-induced amyloidogenic APP processing and A␤ synthesis. Our data indicate that Egr-1 promotes A␤ synthesis via transcriptional activation of BACE-1 and suggest that Egr-1 plays role in activation of BACE-1 and acceleration of A␤ synthesis in AD brain. Egr-1 is a potential therapeutic target for AD.Progressive accumulation of A␤ 2 in the brain is strongly implicated in the pathogenesis of Alzheimer's disease (AD). A␤ is derived from amyloid precursor protein (APP) (1). In the amyloidogenic pathway, APP is cleaved by ␤-secretase (BACE-1) to generate a 99-amino acid membrane-bound protein C99 and soluble APP␤. C99 is further cleaved by ␥-secretase to produce the A␤ peptide. APP is also cleaved by ␣-secretase within the A␤ domain generating an 83-kDa protein C83. Subsequent cleavage of C83 by ␥-secretase generates a nontoxic short peptide P3 containing the C-terminal region of A␤.BACE-1 cleavage of APP is the rate-limiting step in A␤ production. BACE-1 is regarded as the essential enzyme in the A␤ synthesis in the brain (1).A number of studies have shown that the level of BACE-1 protein is significantly up-regulated in AD brain (2-6). It has been suggested that the up-regulation of BACE-1 initiates and/or accelerates A␤ synthesis and promotes AD pathogenesis (1). Determining the mechanism by which BACE-1 is activated in AD brain can provide better understanding of AD pathology and help develop therapies against AD. However, what activates BACE-1 in AD brain is not known. Interestingly, in rat brain, BACE-1 level is elevated following experimental traumatic brain injury (7), transient cerebral ischemia (8), and following occlusion of the middle cerebral artery (9). Oxidative stress induces BACE-1 expression in mouse brains (10) and vascular smooth and HEK-293 cells (11,12). Thus, several cellular events triggered by vascular insults elevate BACE-1 levels in the brain. It has been suggested that the biochemical pathway that is activated by vascular injuries may be involved in up-regulating BAC...

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Section: Discussionmentioning

confidence: 50%

Early Growth Response 1 (Egr-1) Is a Transcriptional Activator of β-Secretase 1 (BACE-1) in the Brain

Qin

Wang

Paudel

2016

Journal of Biological Chemistry

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“…Although there is evidence that variants in Dysf increase risk for AD, and that dysferlin aggregates within Aβ plaques, the effects of Dysf im on the development of AD related pathology in mouse models of AD is not yet known. In the 3xTG mouse, however, levels of Dysf expression are reduced, providing evidence that expression of Dysf is influenced by APP or MAPT transgenes, and/or the development of AD‐related pathology . Further research is needed to establish the mechanism by which dysferlin influences the development of AD‐related pathology in mouse models of AD.…”

Section: Discussionmentioning

confidence: 99%

“…In the 3xTG mouse, however, levels of Dysf expression are reduced, providing evidence that expression of Dysf is influenced by APP or MAPT transgenes, and/or the development of AD-related pathology. 57 Further research is needed to establish the mechanism by which dysferlin influences the development of AD-related pathology in mouse models of AD. 4.5 | What is the mechanism for motor dysfunction in 5xFAD mice?…”

Section: Does Dysf Im Influence the Size Of Motor Phenotypes In 5xfmentioning

confidence: 99%

Age‐related deterioration of motor function in male and female 5xFAD mice from 3 to 16 months of age

O’Leary

Mantolino

Stover

et al. 2018

Genes Brain and Behavior

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Alzheimer's disease (AD) is a neurodegenerative disorder that leads to age‐related cognitive and sensori‐motor dysfunction. There is an increased understanding that motor dysfunction contributes to overall AD severity, and a need to ameliorate these impairments. The 5xFAD mouse develops the neuropathology, cognitive and motor impairments observed in AD, and thus may be a valuable animal model to study motor deficits in AD. Therefore, we assessed age‐related changes in motor ability of male and female 5xFAD mice from 3 to 16 months of age, using a battery of behavioral tests. At 9‐10 months, 5xFAD mice showed reduced body weight, reduced rearing in the open‐field and impaired performance on the rotarod compared to wild‐type controls. At 12‐13 months, 5xFAD mice showed reduced locomotor activity on the open‐field, and impaired balance on the balance beam. At 15‐16 months, impairments were also seen in grip strength. Although sex differences were observed at specific ages, the development of motor dysfunction was similar in male and female mice. Given the 5xFAD mouse is commonly on a C57BL/6 × SJL hybrid background, a subset of mice may be homozygous recessive for the Dysf im mutant allele, which leads to muscular weakness in SJL mice and may exacerbate motor dysfunction. We found small effects of Dysf im on motor function, suggesting that Dysf im contributes little to motor dysfunction in 5xFAD mice. We conclude that the 5xFAD mouse may be a useful model to study mechanisms that produce motor dysfunction in AD, and to assess the efficacy of therapeutics on ameliorating motor impairment.

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“…The model seems particularly suitable for preclinical studies as this AD mouse develops both amyloid-and tau-dependent pathology along with oxidative stress, Ca 2+ and Zn 2+ deregulation, hyperexcitability and also shows an acceleration in the expression of genes that are actively associated with aging (Chakroborty et al, 2012;Gatta et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Pyruvate prevents the development of age-dependent cognitive deficits in a mouse model of Alzheimer's disease without reducing amyloid and tau pathology

Isopi

Granzotto

Corona

et al. 2015

Neurobiology of Disease

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Early and sustained altered expression of aging-related genes in young 3xTg-AD mice

Cited by 39 publications

References 61 publications

Early Growth Response 1 (Egr-1) Is a Transcriptional Activator of β-Secretase 1 (BACE-1) in the Brain

Early Growth Response 1 (Egr-1) Is a Transcriptional Activator of β-Secretase 1 (BACE-1) in the Brain

Age‐related deterioration of motor function in male and female 5xFAD mice from 3 to 16 months of age

Pyruvate prevents the development of age-dependent cognitive deficits in a mouse model of Alzheimer's disease without reducing amyloid and tau pathology

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