Alzheimer's β-Amyloid Peptides Compete for Insulin Binding to the Insulin Receptor

Xie, Lihua; Helmerhorst, Erik; Taddei, Kevin; Plewright, Brian; Bronswijk, Wilhelm van; Martins, Ralph N.

doi:10.1523/jneurosci.22-10-j0001.2002

Cited by 319 publications

(254 citation statements)

References 46 publications

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“…Indeed Ab has been shown to competitively bind to the insulin receptor and inhibit the insulin-induced release of secreted APP products. 193,194 In a transgenic AD model, diet-induced hyperinsulinaemia resulted in accelerated amyloidosis and a reduction in IDE levels. 195 Insulin signalling was also shown to modulate IDE levels in vitro, in a transgenic mouse model and in human AD brain samples.…”

Section: Ab-degrading Enzymesmentioning

confidence: 99%

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

et al. 2008

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Currently, the 'amyloid hypothesis' is the most widely accepted explanation for the pathogenesis of Alzheimer's disease (AD). According to this hypothesis, altered metabolism of the amyloid-b (Ab) peptide is central to the pathological cascade involved in the pathogenesis of AD. Although Ab is produced by almost every cell in the body, a physiological function for the peptide has not been determined, and the pathways by which Ab leads to cognitive dysfunction and cell death are unclear. Numerous therapeutic approaches that target the production, toxicity and removal of Ab are being developed worldwide. Although therapeutic treatment for AD may be imminent, the value and effectiveness of such treatment are largely dependent on early diagnosis of the disease. This review summarizes current knowledge of Ab clearance, transport and degradation, and evaluates the use of such information in the development of diagnostic tools. The conflicting results of plasma Ab ELISAs are discussed, as are the more promising results of Ab imaging by positron emission tomography. Current knowledge of Ab-binding proteins and Ab-degrading enzymes is analysed in the context of a potential therapy for AD. Transport across the blood-brain barrier by the receptor for advanced glycation end products and efflux via the multi-ligand lipoprotein receptor LRP-1 is also reviewed. Enhancing clearance and degradation of Ab remains an attractive therapeutic strategy, and improved understanding of Ab clearance may lead to advances in diagnostics and interventions designed to prevent or delay the onset of AD.

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Section: Ab-degrading Enzymesmentioning

confidence: 99%

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

et al. 2008

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“…Overall, insulin-induced ADDL internalization was observed more routinely in glial-rich cultures prepared from postnatal rat brains. Although binding of ADDLs or A␤ to IR has been detected (35)(36)(37), only a low degree of colocalization between IR and ADDL were seen in neuronal dendrites and astrocytes. This could be explained by rapid loss of the dendritic surface IR upon ADDL binding (37).…”

Section: Expressions Of Ir and Igf-1r Confer On Cells The Capability mentioning

confidence: 97%

“…Converse to the ability of normal IR and IGF-1Rs to mediate a robust clearance of ADDLs, cells with impaired IR and IGF-1R activities show markedly reduced clearance capacity. Reduced ability to clear these potent CNS neurotoxin provides a mechanism that may account, at least in part, for indications that dysfunctional insulin and IGF-1 signaling in the brain contributes to AD pathophysiology (1,2,5,33,(35)(36)(37)60). …”

Section: Expressions Of Ir and Igf-1r Confer On Cells The Capability mentioning

confidence: 99%

“…A Theoretical Pathogenic Loop Involving Insulin Resistance and A␤ Aggregation in AD Pathogenesis-Recently, we and others have observed that A␤ oligomers down-regulate IR function and surface expression, thereby causing brain cell insulin resistance (35)(36)(37)(38). Thus, although normal IR activity helps to defend against the accumulation of toxic A␤ oligomers, the insulin receptors themselves are vulnerable to oligomer-initiated dysfunction.…”

Section: Expressions Of Ir and Igf-1r Confer On Cells The Capability mentioning

confidence: 99%

“…Recently we and others have shown that A␤ oligomers interact with neuronal insulin receptors to cause impairments of the receptor expression and function (35)(36)(37). These impairments mimic the A␤ oligomer-induced synaptic long term potentiation inhibition and can be overcome by insulin treatment (35,38).…”

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Insulin Receptor Dysfunction Impairs Cellular Clearance of Neurotoxic Oligomeric Aβ

Zhao

Lacor

Chen

et al. 2009

Journal of Biological Chemistry

138

101

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Accumulation of amyloid ␤ (A␤) oligomers in the brain is toxic to synapses and may play an important role in memory loss in Alzheimer disease. However, how these toxins are built up in the brain is not understood. In this study we investigate whether impairments of insulin and insulin-like growth factor-1 (IGF-1) receptors play a role in aggregation of A␤. Using primary neuronal culture and immortal cell line models, we show that expression of normal insulin or IGF-1 receptors confers cells with abilities to reduce exogenously applied A␤ oligomers (also known as ADDLs) to monomers. In contrast, transfection of malfunctioning human insulin receptor mutants, identified originally from patient with insulin resistance syndrome, or inhibition of insulin and IGF-1 receptors via pharmacological reagents increases ADDL levels by exacerbating their aggregation. In healthy cells, activation of insulin and IGF-1 receptor reduces the extracellular ADDLs applied to cells via seemingly the insulin-degrading enzyme activity. Although insulin triggers ADDL internalization, IGF-1 appears to keep ADDLs on the cell surface. Nevertheless, both insulin and IGF-1 reduce ADDL binding, protect synapses from ADDL synaptotoxic effects, and prevent the ADDL-induced surface insulin receptor loss. Our results suggest that dysfunctions of brain insulin and IGF-1 receptors contribute to A␤ aggregation and subsequent synaptic loss.Abnormal protein misfolding and aggregation are common features in neurodegenerative diseases such as Alzheimer (AD), 2 Parkinson, Huntington, and prion diseases (1-3). In the AD brain, intracellular accumulation of hyperphosphorylated Tau aggregates and extracellular amyloid deposits comprise the two major pathological hallmarks of the disease (1, 4). A␤ aggregation has been shown to initiate from A␤1-42, a peptide normally cleaved from the amyloid precursor protein (APP) via activities of ␣-and ␥-secretases (5, 6). A large body of evidence in the past decade has indicated that accumulated soluble oligomers of A␤1-42, likely the earliest or intermediate forms of A␤ deposition, are potently toxic to neurons. The toxic effects of A␤ oligomers include synaptic structural deterioration (7,8) and functional deficits such as inhibition of synaptic transmission (9) and synaptic plasticity (10 -13), as well as memory loss (11,14,15). Accumulation of high levels of these oligomers may also trigger inflammatory processes and oxidative stress in the brain probably due to activation of astrocytes and microglia (16,17). Thus, to understand how a physiologically produced peptide becomes a misfolded toxin has been one of the key issues in uncovering the molecular pathogenesis of the disease.A␤ accumulation and aggregation could derive from overproduction or impaired clearance. Mutations of APP or presenilins 1 and 2, for example, are shown to cause overproduction of A␤1-42 and amyloid deposits in the brain of early onset AD (18,19). Because early onset AD accounts for less than 5% of entire AD population, APP and presenilin mutati...

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Roles of Glucagon‐Like Peptide and Glucose‐Dependent Insolinotropic Polypeptide Hormones in Brain Function and Neurodegeneration

Hölscher

2012

Therapeutic Targets

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Alzheimer's β-Amyloid Peptides Compete for Insulin Binding to the Insulin Receptor

Cited by 319 publications

References 46 publications

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

Insulin Receptor Dysfunction Impairs Cellular Clearance of Neurotoxic Oligomeric Aβ

Roles of Glucagon‐Like Peptide and Glucose‐Dependent Insolinotropic Polypeptide Hormones in Brain Function and Neurodegeneration

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