Plaque-Associated Overexpression of Insulin-Degrading Enzyme in the Cerebral Cortex of Aged Transgenic Tg2576 Mice With Alzheimer Pathology

Leal, María Celeste; Dorfman, Verónica Berta; Gamba, Agata Fernández; Frangione, Blas; Wısnıewskı, Thomas; Castaño, Eduardo M.; Sigurdsson, Einar M.; Morelli, Laura

doi:10.1097/01.jnen.0000235853.70092.ba

Cited by 67 publications

(61 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There were lower levels of A ␤ extractable by SDS and FA (insoluble A ␤ ) in the brains of RAGE -/-/arcA ␤ mice at the age of 6 months, but this effect disappeared by the age of 12 months, most probably due to the constant peptide production overwhelming the clearance process. In addition, the observed IDE upregulation resulted from an additive effect of RAGE deletion and the APP transgene or probably A ␤ accumulation, as previously suggested [12,13] . Although it presumably decreased initial A ␤ buildup, the IDE-mediated clearance process did not prevent cognitive decline and eventually became inefficient at the age of 12 months given the similar amounts of cerebral A ␤ in both genotypes.…”

Section: Discussionmentioning

confidence: 51%

RAGE Does Not Affect Amyloid Pathology in Transgenic ArcAβ Mice

Vodopivec¹,

Galichet

Knobloch³

et al. 2009

Neurodegener Dis

View full text Add to dashboard Cite

Background: Alzheimer’s disease (AD) is characterized by brain accumulation of the amyloid-β peptide (Aβ) that triggers a cascade of biochemical and cellular alterations resulting in the clinical phenotype of the disease. While numerous experiments addressed Aβ toxicity, the mechanisms are still not fully understood. The receptor for advanced glycation end products (RAGE) binds Aβ and was suggested to be involved in the pathological processes of AD. Objective: Our purpose was to assess the effect of RAGE deletion on Aβ-related pathology. Methods: We crossed RAGE knockout (RAGE^–/–) mice with transgenic mice harboring both the Swedish and Arctic Aβ precursor protein mutations (arcAβ mice). We assessed Aβ levels, Aβ brain deposition, Aβ-degrading enzyme activities, Aβ precursor protein expression and processing, number and morphology of microglia as well as cognitive performance of 6- and 12-month-old RAGE^–/–/arcAβ, RAGE^–/–, arcAβ and wild-type mice. Results: RAGE^–/–/arcAβ mice had significantly lower levels of SDS- and formic-acid-extracted Aβ in the cortex and hippocampus, with concomitantly increased activity of insulin-degrading enzyme at the age of 6 months. However, RAGE deletion could neither prevent the decline in cognitive performance nor the age-related cerebral accumulation of Aβ peptide. Furthermore, histological analysis revealed no difference in the microglia-occupied brain areas or microglial morphologies between RAGE^–/–/arcAβ and arcAβ mice. Conclusions: Together, our results indicate that while the absence of RAGE was associated with increased insulin-degrading enzyme activity in the brain, it was not sufficient to prevent or ameliorate cognitive deterioration, Aβ accumulation and microglial activation in the arcAβ mouse model of AD.

show abstract

Section: Discussionmentioning

confidence: 51%

RAGE Does Not Affect Amyloid Pathology in Transgenic ArcAβ Mice

Vodopivec¹,

Galichet

Knobloch³

et al. 2009

Neurodegener Dis

View full text Add to dashboard Cite

show abstract

“…The capacity of IDE to degrade Aβ has been recognized for many years (Kurochkin and Goto 1994). The cause of increased IDE may be due partly to activated astrocytes as a result of Aβ-triggered neuroinflammation (Leal et al 2006). Contradictory results regarding IDE expression in the AD brain have been reported (Kim et al 2007).…”

Section: Current State Of Early Diagnosis Of Admentioning

confidence: 96%

Alteration of Aβ metabolism-related molecules in predementia induced by AlCl3 and d-galactose

Sun

Chen

Jiang

et al. 2009

AGE

View full text Add to dashboard Cite

The purpose of this study was to look for alterations in β-amyloid peptide (Aβ) metabolism-related molecules in predementia, the early stage of Alzheimer’s disease (AD). AlCl3 (Al) and d-galactose (D-gal) were used to induce the mouse model for predementia and AD. Protein expression of β-amyloid (Aβ), β-secretase (BACE1), neprilysin (NEP), insulin degrading enzyme (IDE) and receptor for advanced glycation end products (RAGE) in the brain was measured. The results indicated that Al + D-gal induced an AD-like behavioral deficit at 90 days. The period from 45 to 75 days showed no significant behavioral deficit, and we tentatively define this as predementia in this model. A significant increase in BACE1 and decreasing NEP characterized days 45–90 in the cortex and hippocampus. However, high Aβ occurred at day 60. IDE increased from day 60 to day 75. There was no change in RAGE. The results suggest that the observed changes in BACE1, NEP and Aβ in predementia might relate to a different stage of the AD-like pathology, which may be developed into useful biomarkers for the diagnosis of very early AD.

show abstract

“…Neprilysin, a plasma membrane glycoprotein, has a high affinity for Aβ and is present in amyloid plaques, and radiolabelled Aβ 1-42 is catabolized by neprilysin in vivo [33]. Expression of IDE increases around plaques, with age and accumulation of amyloid, in the brains of Tg2576 mice, and mice deficient in neprilysin show increased levels of both Aβ 1-40 and Aβ 1-42 [34,35]. IDE can degrade a number of amyloid-forming peptides, including insulin, Aβ and amylin.…”

Section: Astrocytes and Amyloid Degradation And Clearancementioning

confidence: 98%

The contribution of astrocytes to Alzheimer's disease

Birch

2014

Biochemical Society Transactions

View full text Add to dashboard Cite

Astrocytes were historically classified as supporting cells; however, it is becoming increasingly clear that they actively contribute to neuronal functioning under normal and pathological conditions. As interest in the contribution of neuroinflammation to Alzheimer's disease (AD) progression has grown, manipulating glial cells has become an attractive target for future therapies. Astrocytes have largely been under-represented in studies that assess the role of glia in these processes, despite substantial evidence of astrogliosis in AD. The actual role of astrocytes in AD remains elusive, as they seem to adopt different functions dependent on disease progression and the extent of accompanying parenchymal inflammation. Astrocytes may contribute to the clearance of amyloid β-peptide (Aβ) and restrict the spread of inflammation in the brain. Conversely, they may contribute to neurodegeneration in AD by releasing neurotoxins and neglecting crucial metabolic roles. The present review summarizes current evidence on the multi-faceted functions of astrocytes in AD, highlighting the significant scope available for future therapeutic targets.

show abstract

Plaque-Associated Overexpression of Insulin-Degrading Enzyme in the Cerebral Cortex of Aged Transgenic Tg2576 Mice With Alzheimer Pathology

Cited by 67 publications

References 60 publications

RAGE Does Not Affect Amyloid Pathology in Transgenic ArcAβ Mice

RAGE Does Not Affect Amyloid Pathology in Transgenic ArcAβ Mice

Alteration of Aβ metabolism-related molecules in predementia induced by AlCl3 and d-galactose

The contribution of astrocytes to Alzheimer's disease

Contact Info

Product

Resources

About