Egr1 Expression Is Induced Following Glatiramer Acetate Immunotherapy in Rodent Models of Glaucoma and Alzheimer's Disease

Bakalash, Sharon; Pham, Michael; Koronyo, Yosef; Salumbides, Brenda C.; Kramerov, Andrei A.; Seidenberg, Hillary; Berel, Dror; Black, Keith L.; Koronyo‐Hamaoui, Maya

doi:10.1167/iovs.11-7498

Cited by 40 publications

(58 citation statements)

References 112 publications

(84 reference statements)

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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: 78%

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: 78%

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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“…Furthermore, at this time point, the aminoacyl t-RNA biosynthesis pathway was downregulated, which indicates an alteration of translation and suggest that protein synthesis in the injured retinas is below normal levels, as it has been reported in glaucoma and ischemia. 57,58 One of the most consistent differences observed at 14 days post-IONC was associated with carbohydrate metabolism. Glucose (Glc) and glucose-6-phospate (Glc-6-P) levels were nearly 3-fold higher 14 days post-IONC, whereas additional glycolytic intermediates (3-phosphoglycerate, 2-phospoglycer- ate, and lactate) were slightly higher, but not significantly different from the control ( Table 1, Fig.…”

Section: Discussionmentioning

confidence: 99%

Metabolomic Changes in the Rat Retina After Optic Nerve Crush

Agudo‐Barriuso

Lahoz

Nadal-Nicolás

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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Citation: Agudo-Barriuso M, Lahoz A, Nadal-Nicolás FM, et al. Metabolomic changes in the rat retina after optic nerve crush. Invest Ophthalmol Vis Sci. 2013;54:4249-4259. DOI:10.1167/iovs.12-11451 PURPOSE. To identify metabolic pathways and metabolites affected by optic nerve crush that can act as predictors of the disease or therapeutic targets. METHODS.The left optic nerve of adult rats was intraorbitally crushed and retinas were dissected 24 hours or 14 days after the lesion (n ¼ 10 per group). Metabolic profiling analysis was carried out by Metabolon, Inc. A total of 195 metabolites were unambiguously detected. Data were normalized and the regulated metabolites were identified after comparing the different conditions. Metabolite concentration changes were analyzed using single and multivariate statistical analysis to detect discriminatory metabolites. Functional clustering and meta-analysis of the regulated metabolites was run through the Metacore platform. RESULTS.Comparison of 24 hours versus control, 14 days versus control samples, and 24 hours versus 14 days identified 9, 19, and 32 regulated metabolites, respectively. Single and multivariate analysis identified a total of 27 and 36 metabolites to discriminate between control and 14 days and between 24 hours and 14 days, respectively. Enrichment analysis showed alterations in the amino acid, carbohydrate, and lipid metabolism, which were further linked to translation, oxidative stress, energy (glucose and tricarboxylic acid cycle), and apoptosis through ceramide pathways.CONCLUSIONS. Our analysis differentiates a set of metabolites that clearly discriminate control and early-injury samples from late-injury samples. These metabolites could have potential use as diagnostic molecules.

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“…Macrophages readily absorb amyloid fibrils in vitro (59,60) and seem more efficient than microglia at restricting Aβ plaques in models of AD (30, 31, 36, 38). ADtg mice immunized with glatiramer acetate or DCs loaded with the peptide MOG45D had an increased cerebral infiltration of monocytes that resulted in substantial attenuation of AD pathology (31,36,61). These mice also had reduced cognitive impairment (62).…”

Section: Discussionmentioning

confidence: 99%

“…For brain-soluble and -insoluble ELISA analysis, brain tissues were homogenized in PBS buffer with 0.5% Triton X-100 and a 1X protease inhibitor cocktail set I (Calbiochem). After removal of cell debris, the homogenate was centrifuged at 10,000 g for 20 minutes at 4°C (36,61). The supernatant was considered the soluble fraction and was used to assess soluble Aβ.…”

Section: Methodsmentioning

confidence: 99%

Angiotensin-converting enzyme overexpression in myelomonocytes prevents Alzheimer’s-like cognitive decline

Bernstein¹,

Koronyo²,

Salumbides³

et al. 2014

J. Clin. Invest.

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Cognitive decline in patients with Alzheimer's disease (AD) is associated with elevated brain levels of amyloid β protein (Aβ), particularly neurotoxic Aβ 1-42 . Angiotensin-converting enzyme (ACE) can degrade Aβ 1-42 , and ACE overexpression in myelomonocytic cells enhances their immune function. To examine the effect of targeted ACE overexpression on AD, we crossed ACE 10/10 mice, which overexpress ACE in myelomonocytes using the c-fms promoter, with the transgenic APP SWE /PS1 ΔE9 mouse model of AD (AD + ). Evaluation of brain tissue from these AD + ACE 10/10 mice at 7 and 13 months revealed that levels of both soluble and insoluble brain Aβ 1-42 were reduced compared with those in AD + mice. Furthermore, both plaque burden and astrogliosis were drastically reduced. Administration of the ACE inhibitor ramipril increased Aβ levels in AD + ACE 10/10 mice compared with the levels induced by the ACE-independent vasodilator hydralazine. Overall, AD + ACE 10/10 mice had less brain-infiltrating cells, consistent with reduced AD-associated pathology, though ACE-overexpressing macrophages were abundant around and engulfing Aβ plaques. At 11 and 12 months of age, the AD + ACE 10/WT and AD + ACE 10/10 mice were virtually equivalent to non-AD mice in cognitive ability, as assessed by maze-based behavioral tests. Our data demonstrate that an enhanced immune response, coupled with increased myelomonocytic expression of catalytically active ACE, prevents cognitive decline in a murine model of AD.

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Egr1 Expression Is Induced Following Glatiramer Acetate Immunotherapy in Rodent Models of Glaucoma and Alzheimer's Disease

Abstract: This study presents global gene expression profiles associated with GA immunization in a glaucoma rat model. Moreover, it identifies EGR1 transcription factor as a potential mediator for GA-induced neuroprotection in both glaucoma and AD.

Cited by 40 publications

References 112 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

Metabolomic Changes in the Rat Retina After Optic Nerve Crush

Angiotensin-converting enzyme overexpression in myelomonocytes prevents Alzheimer’s-like cognitive decline

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