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Mechanisms underlying insulin deficiency-induced acceleration of β-amyloidosis in a mouse model of Alzheimer's disease.

Devi L, Alldred MJ, Ginsberg SD, Ohno M - PLoS ONE (2012)

Bottom Line: Although evidence is accumulating that diabetes mellitus is an important risk factor for sporadic Alzheimer's disease (AD), the mechanisms by which defects in insulin signaling may lead to the acceleration of AD progression remain unclear.Moreover, STZ treatments did not affect levels of Aβ-degrading enzymes such as neprilysin and insulin-degrading enzyme (IDE) in 5XFAD brains.Taken together, our findings provide a mechanistic foundation for a link between diabetes and AD by demonstrating that insulin deficiency may change APP processing to favor β-amyloidogenesis via the translational upregulation of BACE1 in combination with elevations in its substrate, APP.

View Article: PubMed Central - PubMed

Affiliation: Center for Dementia Research, Nathan Kline Institute, Orangeburg, New York, United States of America.

ABSTRACT
Although evidence is accumulating that diabetes mellitus is an important risk factor for sporadic Alzheimer's disease (AD), the mechanisms by which defects in insulin signaling may lead to the acceleration of AD progression remain unclear. In this study, we applied streptozotocin (STZ) to induce experimental diabetes in AD transgenic mice (5XFAD model) and investigated how insulin deficiency affects the β-amyloidogenic processing of amyloid precursor protein (APP). Two and half months after 5XFAD mice were treated with STZ (90 mg/kg, i.p., once daily for two consecutive days), they showed significant reductions in brain insulin levels without changes in insulin receptor expression. Concentrations of cerebral amyloid-β peptides (Aβ40 and Aβ42) were significantly increased in STZ-treated 5XFAD mice as compared with vehicle-treated 5XFAD controls. Importantly, STZ-induced insulin deficiency upregulated levels of both β-site APP cleaving enzyme 1 (BACE1) and full-length APP in 5XFAD mouse brains, which was accompanied by dramatic elevations in the β-cleaved C-terminal fragment (C99). Interestingly, BACE1 mRNA levels were not affected, whereas phosphorylation of the translation initiation factor eIF2α, a mechanism proposed to mediate the post-transcriptional upregulation of BACE1, was significantly elevated in STZ-treated 5XFAD mice. Meanwhile, levels of GGA3, an adapter protein responsible for sorting BACE1 to lysosomal degradation, are indistinguishable between STZ- and vehicle-treated 5XFAD mice. Moreover, STZ treatments did not affect levels of Aβ-degrading enzymes such as neprilysin and insulin-degrading enzyme (IDE) in 5XFAD brains. Taken together, our findings provide a mechanistic foundation for a link between diabetes and AD by demonstrating that insulin deficiency may change APP processing to favor β-amyloidogenesis via the translational upregulation of BACE1 in combination with elevations in its substrate, APP.

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Related in: MedlinePlus

Effects of STZ-induced insulin deficiency on neprilysin and IDE levels in 5XFAD mice.(A) Western blot analysis of hemibrain lysates from vehicle- and STZ-treated 5XFAD mice. (B) Immunoreactive bands for neprilysin and IDE were quantified and expressed as the percentage of vehicle-treated 5XFAD levels (n = 4–7 mice per group). There was no difference in neprilysin or IDE levels between STZ- and vehicle-treated 5XFAD mice. All data are presented as mean ± SEM.
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pone-0032792-g004: Effects of STZ-induced insulin deficiency on neprilysin and IDE levels in 5XFAD mice.(A) Western blot analysis of hemibrain lysates from vehicle- and STZ-treated 5XFAD mice. (B) Immunoreactive bands for neprilysin and IDE were quantified and expressed as the percentage of vehicle-treated 5XFAD levels (n = 4–7 mice per group). There was no difference in neprilysin or IDE levels between STZ- and vehicle-treated 5XFAD mice. All data are presented as mean ± SEM.

Mentions: In addition to the facilitation of β-amyloidogenesis through BACE1 and APP elevations, it is possible that changes in the Aβ metabolism may also contribute to increases in Aβ40 and Aβ42 levels in STZ-treated 5XFAD mice. Therefore, we examined whether STZ treatments may affect neprilysin and/or IDE, key enzymes responsible for the degradation and clearance of Aβ peptides [38], [39], in 5XAFD mice (Fig. 4A). However, levels of neprilysin and IDE were indistinguishable between STZ- and vehicle-treated 5XFAD mouse brains (Fig. 4B), suggesting that increased levels of Aβ accumulation in insulin-deficient diabetic 5XFAD mice do not result from alterations in these Aβ-degrading enzymes.


Mechanisms underlying insulin deficiency-induced acceleration of β-amyloidosis in a mouse model of Alzheimer's disease.

Devi L, Alldred MJ, Ginsberg SD, Ohno M - PLoS ONE (2012)

Effects of STZ-induced insulin deficiency on neprilysin and IDE levels in 5XFAD mice.(A) Western blot analysis of hemibrain lysates from vehicle- and STZ-treated 5XFAD mice. (B) Immunoreactive bands for neprilysin and IDE were quantified and expressed as the percentage of vehicle-treated 5XFAD levels (n = 4–7 mice per group). There was no difference in neprilysin or IDE levels between STZ- and vehicle-treated 5XFAD mice. All data are presented as mean ± SEM.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3293895&req=5

pone-0032792-g004: Effects of STZ-induced insulin deficiency on neprilysin and IDE levels in 5XFAD mice.(A) Western blot analysis of hemibrain lysates from vehicle- and STZ-treated 5XFAD mice. (B) Immunoreactive bands for neprilysin and IDE were quantified and expressed as the percentage of vehicle-treated 5XFAD levels (n = 4–7 mice per group). There was no difference in neprilysin or IDE levels between STZ- and vehicle-treated 5XFAD mice. All data are presented as mean ± SEM.
Mentions: In addition to the facilitation of β-amyloidogenesis through BACE1 and APP elevations, it is possible that changes in the Aβ metabolism may also contribute to increases in Aβ40 and Aβ42 levels in STZ-treated 5XFAD mice. Therefore, we examined whether STZ treatments may affect neprilysin and/or IDE, key enzymes responsible for the degradation and clearance of Aβ peptides [38], [39], in 5XAFD mice (Fig. 4A). However, levels of neprilysin and IDE were indistinguishable between STZ- and vehicle-treated 5XFAD mouse brains (Fig. 4B), suggesting that increased levels of Aβ accumulation in insulin-deficient diabetic 5XFAD mice do not result from alterations in these Aβ-degrading enzymes.

Bottom Line: Although evidence is accumulating that diabetes mellitus is an important risk factor for sporadic Alzheimer's disease (AD), the mechanisms by which defects in insulin signaling may lead to the acceleration of AD progression remain unclear.Moreover, STZ treatments did not affect levels of Aβ-degrading enzymes such as neprilysin and insulin-degrading enzyme (IDE) in 5XFAD brains.Taken together, our findings provide a mechanistic foundation for a link between diabetes and AD by demonstrating that insulin deficiency may change APP processing to favor β-amyloidogenesis via the translational upregulation of BACE1 in combination with elevations in its substrate, APP.

View Article: PubMed Central - PubMed

Affiliation: Center for Dementia Research, Nathan Kline Institute, Orangeburg, New York, United States of America.

ABSTRACT
Although evidence is accumulating that diabetes mellitus is an important risk factor for sporadic Alzheimer's disease (AD), the mechanisms by which defects in insulin signaling may lead to the acceleration of AD progression remain unclear. In this study, we applied streptozotocin (STZ) to induce experimental diabetes in AD transgenic mice (5XFAD model) and investigated how insulin deficiency affects the β-amyloidogenic processing of amyloid precursor protein (APP). Two and half months after 5XFAD mice were treated with STZ (90 mg/kg, i.p., once daily for two consecutive days), they showed significant reductions in brain insulin levels without changes in insulin receptor expression. Concentrations of cerebral amyloid-β peptides (Aβ40 and Aβ42) were significantly increased in STZ-treated 5XFAD mice as compared with vehicle-treated 5XFAD controls. Importantly, STZ-induced insulin deficiency upregulated levels of both β-site APP cleaving enzyme 1 (BACE1) and full-length APP in 5XFAD mouse brains, which was accompanied by dramatic elevations in the β-cleaved C-terminal fragment (C99). Interestingly, BACE1 mRNA levels were not affected, whereas phosphorylation of the translation initiation factor eIF2α, a mechanism proposed to mediate the post-transcriptional upregulation of BACE1, was significantly elevated in STZ-treated 5XFAD mice. Meanwhile, levels of GGA3, an adapter protein responsible for sorting BACE1 to lysosomal degradation, are indistinguishable between STZ- and vehicle-treated 5XFAD mice. Moreover, STZ treatments did not affect levels of Aβ-degrading enzymes such as neprilysin and insulin-degrading enzyme (IDE) in 5XFAD brains. Taken together, our findings provide a mechanistic foundation for a link between diabetes and AD by demonstrating that insulin deficiency may change APP processing to favor β-amyloidogenesis via the translational upregulation of BACE1 in combination with elevations in its substrate, APP.

Show MeSH
Related in: MedlinePlus