Neuronal IGF-1 resistance reduces A beta accumulation and protects against premature death in a model of Alzheimer's disease
ABSTRACT Alzheimer's disease (AD) is characterized by progressive neurodegeneration leading to loss of cognitive abilities and ultimately to death. Postmortem investigations revealed decreased expression of cerebral insulin-like growth factor (IGF)-1 receptor (IGF-1R) and insulin receptor substrate (IRS) proteins in patients with AD. To elucidate the role of insulin/IGF-1 signaling in AD, we crossed mice expressing the Swedish mutation of amyloid precursor protein (APP(SW), Tg2576 mice) as a model for AD with mice deficient for either IRS-2, neuronal IGF-1R (nIGF-1R(-/-)), or neuronal insulin receptor (nIR(-/-)), and analyzed survival, glucose, and APP metabolism. In the present study, we show that IRS-2 deficiency in Tg2576 mice completely reverses premature mortality in Tg2576 females and delays beta-amyloid (Abeta) accumulation. Analysis of APP metabolism suggested that delayed Abeta accumulation resulted from decreased APP processing. To delineate the upstream signal responsible for IRS-2-mediated disease protection, we analyzed mice with nIGF-1R or nIR deficiency predominantly in the hippocampus. Interestingly, both male and female nIGF-1R(-/-)Tg2576 mice were protected from premature death in the presence of decreased Abeta accumulation specifically in the hippocampus formation. However, neuronal IR deletion had no influence on lethality of Tg2576 mice. Thus, impaired IGF-1/IRS-2 signaling prevents premature death and delays amyloid accumulation in a model of AD.
SourceAvailable from: Paula I Moreira
Chapter: THE JANUS FACE OF INSULIN IN BRAIN[Show abstract] [Hide abstract]
ABSTRACT: Insulin and its receptors (IR) are widely distributed throughout the central nervous system (CNS). Although central insulin is mainly from periphery, some evidence implicates de novo synthesis at the CNS. Important studies recently reported that insulin exerts a neuroprotective effect and that decreased brain insulin levels and/or IR-mediated signaling are linked to several age-related neurodegenerative diseases. These findings were further potentiated by the recent hypothesis that insulin may constitute the potential missing link between diabetes and Alzheimer disease (AD) in the CNS, resulting in AD being called "type 3 diabetes." In this regard, insulin could be a very promising therapy against diabetes-and age-related neurodegenerative diseases. However, some studies (including longevity ones) have given controversial results on the beneficial effects of CNS insulin/IR activity. Herewith, we aim to critically analyze the pros and cons of insulin in the CNS, especially regarding age-and diabetes-related neurodegeneration.Metabolic Syndrome and Neurological Disorders, Edited by Akhlaq A. Farooqui, Tahira Farooqui, 01/2013: chapter 5: pages 85-113; Wiley-Blackwell.
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ABSTRACT: Numerous disorders, including neurodegenerative diseases and certain types of cancer, manifest late in life. This common feature raises the prospect that an aging-associated decline in the activity of cellular and organismal maintenance mechanisms enables the emergence of these maladies in late life stages. Accordingly, the alteration of aging bears the promise of harnessing the mechanisms that protect the young organism to prevent illness in the elderly. The identification of aging-regulatory pathways has enabled scrutiny of this hypothesis and revealed that the alteration of aging protects invertebrates and mammals from toxic protein aggregation linked to neurodegeneration and from cancer. Here we review the current knowledge on the regulation of aging at the cellular and organismal levels, delineate the mechanistic links between aging and late-onset disorders, describe efforts to develop compounds that protect from these maladies by selectively manipulating aging, and discuss future research directions and possible therapeutic implications of this approach. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease Volume 10 is January 24, 2015. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.Annual Review of Pathology Mechanisms of Disease 10/2014; DOI:10.1146/annurev-pathol-012414-040508 · 22.13 Impact Factor
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ABSTRACT: The pathogenesis of Alzheimer disease (AD) is characterized by the aggregation of amyloid-β (Aβ) peptides leading to deposition of senile plaques and a progressive decline of cognitive functions, which currently remains the main criterion for its diagnosis. Robust biomarkers for AD do not yet exist, although changes in the cerebrospinal fluid levels of tau and Aβ represent promising candidates in addition to brain imaging and genetic risk profiling. Although concentrations of soluble Aβ42 correlate with symptoms of AD, less is known about the biological activities of Aβ peptides which are generated from the amyloid-β protein precursor. An unbiased DNA microarray study showed that Aβ42, at sub-lethal concentrations, specifically increases expression of several genes in neuroblastoma cells, notably the insulin-like growth factor binding proteins 3 and 5 (IGFBP3/5), the transcription regulator inhibitor of DNA binding, and the transcription factor Lim only domain protein 4. Using qRT-PCR, we confirmed that mRNA levels of the identified candidate genes were exclusively increased by the potentially neurotoxic Aβ42 wild-type peptide, as both the less toxic Aβ40 and a non-toxic substitution peptide Aβ42 G33A did not affect mRNA levels. In vivo immunohistochemistry revealed a corresponding increase in both hippocampal and cortical IGFBP5 expression in an AD mouse model. Proteomic analyses of human AD cerebrospinal fluid displayed increased in vivo concentrations of IGFBPs. IGFBPs and transcription factors, as identified here, are modulated by soluble Aβ42 and may represent useful early biomarkers.Journal of Alzheimer's disease: JAD 10/2014; 44(2). DOI:10.3233/JAD-141902 · 3.61 Impact Factor