Insulin increases CSF Aβ42 levels in normal older adults

Watson, G. Stennis; Peskind, Elaine R.; Asthana, Sanjay; Purganan, Kristina; Wait, C.; Chapman, Douglas; Schwartz, Michael W.; Plymate, Stephen R.; Craft, Suzanne

doi:10.1212/01.wnl.0000065916.25128.25

Cited by 252 publications

(162 citation statements)

References 33 publications

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“…185,207 In addition, insulin infusion increases Ab1-42 levels in human CSF in an age-dependent manner. 208 Platelets are a potential source of this insulin response, as they are capable of releasing Ab and are particularly responsive to insulin through a functional insulin receptor. Furthermore, hyperinsulinaemia is associated with increased platelet activation.…”

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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“…In addition, the plasmatic levels of its cognate ligand, insulin, increase during aging, most likely because of progressive peripheral resistance. Insulin resistance is also a risk-factor for AD [18,49] and has been implicated with several aspects of AD neuropathology [18], including production/secretion of Aβ [18,31,49,161].…”

Section: Insulin/igf1 Receptors: a Signaling Pathway For The General mentioning

confidence: 99%

Aging of the brain, neurotrophin signaling, and Alzheimer's disease: Is IGF1-R the common culprit?

Puglielli¹

2008

Neurobiology of Aging

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The last decade has revealed that the lifespan of an organism can be modulated by the signaling pathway that acts downstream of the insulin/insulin-like growth factor 1 receptors (IR/IGF1-R), indicating that there is a "program" that drives the process of aging. New results have now linked the same pathway to the neurogenic capacities of the aging brain, to neurotrophin signaling, and to the molecular pathogenesis of Alzheimer's disease. Therefore, a common signaling cascade now seems to link aging to age-associated pathologies of the brain, suggesting that pharmacologic approaches aimed at the modulation of this pathway can serve to delay the onset of age-associated disorders and improve the quality of life. Work from a wide range of fields performed with different approaches has already identified some of the signaling molecules that act downstream of IGF1-R, and has revealed that a delicate checkpoint exists to balance excessive growth/"immortality" and reduced growth/"senescence" of a cell. Future research will determine how far the connection goes and how much of it we can influence.

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“…This effect is perhaps explained by the elevation in serum insulin levels (as observed in prediabetes and early T2DM), which has been associated with impaired cognitive function [53] . This might be due to elevated Aβ levels, which are associated with elevated serum insulin content [54] . Recent research suggests that high-cholesterol could promote the synthesis of Aβ, and lower cholesterol by blocking the 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibits the Aβ production [55] .…”

Section: Commonality Between T2dm and Admentioning

confidence: 99%

Is Glucagon-like peptide-1, an agent treating diabetes, a new hope for Alzheimer’s disease?

Lin

2007

Neurosci. Bull.

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Glucagon-like peptide-1 (GLP-1) has been endorsed as a promising and attractive agent in the treatment of type 2 diabetes mellitus (T2DM). Both Alzheimer's disease (AD) and T2DM share some common pathophysiologic hallmarks, such as amyloid β (Aβ), phosphoralation of tau protein, and glycogen synthase kinase-3. GLP-1 possesses neurotropic properties and can reduce amyloid protein levels in the brain. Based on extensive studies during the past decades, the understanding on AD leads us to believe that the primary targets in AD are the Aβ and tau protein. Combine these findings, GLP-1 is probably a promising agent in the therapy of AD. This review was focused on the biochemistry and physiology of GLP-1, communities between T2DM and AD, new progresses of GLP -1 in treating T2MD and improving some pathologic hallmarks of AD.

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Insulin increases CSF Aβ42 levels in normal older adults

Abstract: These findings are consistent with recent in vitro studies of insulin effects on Abeta and support the notion that insulin may modulate Abeta42 levels acutely in humans.

Cited by 252 publications

References 33 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

Aging of the brain, neurotrophin signaling, and Alzheimer's disease: Is IGF1-R the common culprit?

Is Glucagon-like peptide-1, an agent treating diabetes, a new hope for Alzheimer’s disease?

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