Detergent resistant membrane-associated IDE in brain tissue and cultured cells: Relevance to Aβ and insulin degradation

Bulloj, Ayelen; Leal, María Celeste; Surace, Ezequiel; Zhang, Xue; Xu, Huaxi; Ledesma, María Dolores; Castaño, Eduardo M.; Morelli, Laura

doi:10.1186/1750-1326-3-22

Cited by 41 publications

(40 citation statements)

References 58 publications

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“…An association of IDE with endosomes and detergent-resistant membrane microdomains, which are enriched in endosomal compartments, has been reported recently (61). MVBs are intrinsic components of the endosomal system and formed by the inward budding of endosomal membranes (38,40).…”

Section: Discussionmentioning

confidence: 89%

Statins Promote the Degradation of Extracellular Amyloid β-Peptide by Microglia via Stimulation of Exosome-associated Insulin-degrading Enzyme (IDE) Secretion

Tamboli

Barth

Christian

et al. 2010

Journal of Biological Chemistry

197

163

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Epidemiological studies indicate that intake of statins decrease the risk of developing Alzheimer disease. Cellular and in vivo studies suggested that statins might decrease the generation of the amyloid ␤-peptide (A␤) from the ␤-amyloid precursor protein. Here, we show that statins potently stimulate the degradation of extracellular A␤ by microglia. The statin-dependent clearance of extracellular A␤ is mainly exerted by insulindegrading enzyme (IDE) that is secreted in a nonconventional pathway in association with exosomes. Stimulated IDE secretion and A␤ degradation were also observed in blood of mice upon peripheral treatment with lovastatin. Importantly, increased IDE secretion upon lovastatin treatment was dependent on protein isoprenylation and up-regulation of exosome secretion by fusion of multivesicular bodies with the plasma membrane. These data demonstrate a novel pathway for the nonconventional secretion of IDE via exosomes. The modulation of this pathway could provide a new strategy to enhance the extracellular clearance of A␤. Alzheimer disease (AD)3 is associated with extracellular deposits of the amyloid ␤-peptide (A␤) and intraneuronal aggregates of hyperphosphorylated Tau protein in the brain (1). Evidence suggests that the pathogenesis of AD involves deleterious neurotoxic effects of aggregated A␤ peptides (2), which are derived by sequential proteolytic processing of the ␤-amyloid precursor protein (APP) by ␤-and ␥-secretases (3). APP can also be cleaved in a nonamyloidogenic pathway that involves initial cleavage by ␣-secretase within the A␤ domain that precludes the later generation of A␤ peptides (4). Brain A␤ levels are not only determined by the rate of production but also by different clearance mechanisms, including receptor-mediated endocytosis/phagocytosis and subsequent degradation in the endosomal/lysosomal compartment, transcytosis via the blood-brain barrier, as well as proteolytic degradation of extracellular A␤ by cell surface-localized and secreted proteases (5-10).Several studies indicated a dysregulation of lipid metabolism as an important aspect of AD-associated neurodegeneration. In particular, increased cholesterol levels seem to correlate with increased AD risk. Retrospective studies revealed the beneficial effects of statins (11). However, molecular mechanisms by which statins could offer protection against AD remain to be characterized in detail (12, 13). Most studies with cultured cells and animal models indicate that statin-mediated inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) could decrease the generation of A␤ by promoting nonamyloidogenic processing of APP. Other studies also showed that extraction of cholesterol from cellular membranes by cyclodextrins differentially affects A␤ generation. Although strong reduction of cholesterol decreased A␤ generation, a moderate extraction rather promoted the secretion of A␤. These effects were attributed to alterations in the distribution of APP and secretases within membrane microdomains (14 -18). In ...

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Section: Discussionmentioning

confidence: 89%

Statins Promote the Degradation of Extracellular Amyloid β-Peptide by Microglia via Stimulation of Exosome-associated Insulin-degrading Enzyme (IDE) Secretion

Tamboli

Barth

Christian

et al. 2010

Journal of Biological Chemistry

197

163

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show abstract

“…3A). It has been reported that there are two pools of IDE: a cytosolic pool with a longer half-life and a plasma membrane pool that shows faster turn-over [54]. The membrane-bound IDE protein level is important because its level is related to the clearance of A␤ plaques in A␤PP transgenic mice [55] and its decrease in the brain of individuals is associated with a high risk of developing AD [56].…”

Section: Discussionmentioning

confidence: 99%

Cooperative Therapeutic Action of Retinoic Acid Receptor and Retinoid X Receptor Agonists in a Mouse Model of Alzheimer's Disease

Kawahara

Suenobu

Ohtsuka

et al. 2014

JAD

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Abstract. Alzheimer's disease (AD) is a neurodegenerative process involving amyloid-␤ (A␤) peptide deposition, neuroinflammation, and progressive memory loss. Here, we evaluated whether oral administration of retinoic acid receptor (RAR)␣,␤ agonist Am80 (tamibarotene) or specific retinoid X receptor (RXR) pan agonist HX630 or their combination could improve deficits in an AD model, 8.5-month-old amyloid-␤ protein precursor 23 (A␤PP23) mice. Co-administration of Am80 (0.5 mg/kg) and HX630 (5 mg/kg) for 17 days significantly improved memory deficits (Morris water maze) in A␤PP23 mice, whereas administration of either agent alone produced no effect. Only co-administration significantly reduced the level of insoluble A␤ peptide in the brain. These results thus indicate that effective memory improvement via reduction of insoluble A␤ peptide in 8.5-month-old A␤PP23 mice requires co-activation of RAR␣,␤ and RXRs. RAR␣-positive microglia accumulated A␤ plaques in the A␤PP23 mice. Rat primary microglia co-treated with Am80/HX630 showed increased degradation activity towards 125 I-labeled oligomeric A␤ 1-42 peptide in an insulin-degrading enzyme (IDE)-dependent manner. The co-administration increased mRNA for IDE and membrane-associated IDE protein in vivo, suggesting that IDE contributes to A␤ clearance in Am80/HX630-treated A␤PP23 mice. Am80/HX630 also increased IL-4R␣ expression in microglial MG5 cells. The improvement in memory of Am80/HX630-treated A␤PP23 mice was correlated with the levels and signaling of hippocampal interleukin-4 (IL-4). Therefore, Am80/HX630 may promote differentiation of IL-4-responsive M2-like microglia and increase their activity for clearance of oligomeric A␤ peptides by restoring impaired IL-4 signaling in A␤PP23 mice. Combination treatment with RAR and RXR agonists may be an effective approach for AD therapy.

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“…These include insulin, glucagon, and insulin-like growth factors I and II, and IDE also converts β-endorphin to γ-endorphin [130, 131]. Interestingly, the enzyme does not contain an obvious signal sequence and is mostly intracellular, yet reports suggest that IDE, in neurons, may be membrane-associated and even secreted into the medium [132, 133]. However, it remains unclear whether IDE is secreted or simply released from damaged cells.…”

Section: Other Pathways For Aβ Turnovermentioning

confidence: 99%

Amyloid-Beta Protein Clearance and Degradation (ABCD) Pathways and their Role in Alzheimer’s Disease

Baranello¹,

Bharani²,

Padmaraju³

et al. 2015

CAR

266

196

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Amyloid-β proteins (Aβ) of 42 (Aβ42) and 40 aa (Aβ40) accumulate as senile plaques (SP) and cerebrovascular amyloid protein deposits that are defining diagnostic features of Alzheimer’s disease (AD). A number of rare mutations linked to familial AD (FAD) on the Aβ precursor protein (APP), Presenilin-1 (PS1), Presenilin-2 (PS2), Adamalysin10, and other genetic risk factors for sporadic AD such as the ε4 allele of Apolipoprotein E (ApoE-ε4) foster the accumulation of Aβ and also induce the entire spectrum of pathology associated with the disease. Aβ accumulation is therefore a key pathological event and a prime target for the prevention and treatment of AD. APP is sequentially processed by β-site APP cleaving enzyme (BACE1) and γ-secretase, a multisubunit PS1/PS2-containing integral membrane protease, to generate Aβ. Although Aβ accumulates in all forms of AD, the only pathways known to be affected in FAD increase Aβ production by APP gene duplication or via base substitutions on APP and γ-secretase subunits PS1 and PS2 that either specifically increase the yield of the longer Aβ42 or both Aβ40 and Aβ42. However, the vast majority of AD patients accumulate Aβ without these known mutations. This led to proposals that impairment of Aβ degradation or clearance may play a key role in AD pathogenesis. Several candidate enzymes, including Insulin-degrading enzyme (IDE), Neprilysin (NEP), Endothelin-converting enzyme (ECE), Angiotensin converting enzyme (ACE), Plasmin, and Matrix metalloproteinases (MMPs) have been identified and some have even been successfully evaluated in animal models. Several studies also have demonstrated the capacity of γ-secretase inhibitors to paradoxically increase the yield of Aβ and we have recently established that the mechanism is by skirting Aβ degradation. This review outlines major cellular pathways of Aβ degradation to provide a basis for future efforts to fully characterize the panel of pathways responsible for Aβ turnover.

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Detergent resistant membrane-associated IDE in brain tissue and cultured cells: Relevance to Aβ and insulin degradation

Cited by 41 publications

References 58 publications

Statins Promote the Degradation of Extracellular Amyloid β-Peptide by Microglia via Stimulation of Exosome-associated Insulin-degrading Enzyme (IDE) Secretion

Statins Promote the Degradation of Extracellular Amyloid β-Peptide by Microglia via Stimulation of Exosome-associated Insulin-degrading Enzyme (IDE) Secretion

Cooperative Therapeutic Action of Retinoic Acid Receptor and Retinoid X Receptor Agonists in a Mouse Model of Alzheimer's Disease

Amyloid-Beta Protein Clearance and Degradation (ABCD) Pathways and their Role in Alzheimer’s Disease

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