Blockade of the insulin-like growth factor I receptor in the choroid plexus originates Alzheimer's-like neuropathology in rodents: New cues into the human disease?

Carro, Eva; Trejo, José Luís; Spuch, Carlos; Bohl, Delphine; Heard, Jean Michel; Torres‐Alemán, Ignacio

doi:10.1016/j.neurobiolaging.2005.09.039

Cited by 126 publications

(100 citation statements)

References 58 publications

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“…These findings also suggest that targeting megalin expression may be an effective therapeutic strategy for treating AD. Because modulating the activity of the IGF-IR at the choroid plexus originates a similar pattern of biochemical and functional modifications in the brain (Carro et al, 2005b), we conclude that the IGF-IR/megalin pathway in the choroid plexus is of remarkable neuroprotective significance.…”

Section: Discussionmentioning

confidence: 80%

Choroid Plexus Megalin Is Involved in Neuroprotection by Serum Insulin-Like Growth Factor I

Carro¹,

Spuch²,

Trejo³

et al. 2005

J. Neurosci.

186

163

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The involvement of circulating insulin-like growth factor I (IGF-I) in the beneficial effects of physical exercise on the brain makes this abundant serum growth factor a physiologically relevant neuroprotective signal. However, the mechanisms underlying neuroprotection by serum IGF-I remain primarily unknown. Among many other neuroprotective actions, IGF-I enhances clearance of brain amyloid ␤ (A␤) by modulating transport/production of A␤ carriers at the blood-brain interface in the choroid plexus. We found that physical exercise increases the levels of the choroid plexus endocytic receptor megalin/low-density lipoprotein receptor-related protein-2 (LRP2), a multicargo transporter known to participate in brain uptake of A␤ carriers. By manipulating choroid plexus megalin levels through viral-directed overexpression and RNA interference, we observed that megalin mediates IGF-I-induced clearance of A␤ and is involved in IGF-I transport into the brain. Through this dual role, megalin participates in the neuroprotective actions of IGF-I including prevention of tau hyperphosphorylation and maintenance of cognitive function in a variety of animal models of cognitive loss. Because we found that in normal aged animals, choroid plexus megalin/LRP2 is decreased, an attenuated IGF-I/megalin input may contribute to increased risk of neurodegeneration, including late-onset Alzheimer's disease.

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Section: Discussionmentioning

confidence: 80%

Choroid Plexus Megalin Is Involved in Neuroprotection by Serum Insulin-Like Growth Factor I

Carro¹,

Spuch²,

Trejo³

et al. 2005

J. Neurosci.

186

163

View full text Add to dashboard Cite

show abstract

“…Blockade of IGF-1 receptors in the choroid plexus induced AD-like pathology and cognitive impairment in rodents and accelerated Ab pathology in transgenic mice. 183 Conversely, administration of IGF-1 to aged transgenic mice improved cognitive performance, reduced AD-like pathology and increased the amount of Ab bound to carrier proteins. 184 Although the effects of IGF-1 may not be solely attributable to enhancing Ab efflux from CNS, these beneficial effects support a possible therapeutic role of IGF-1 for AD.…”

Section: Ab Clearance Mechanismsmentioning

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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“…In fact, IGF1 can protect from cell death in vitro (even in cells that do not express IGF1-R) and can exert neuroprotective effects in vivo (reviewed in [20]). Some of the neuroprotective effects documented in vivo seem to involve the cell-surface receptor megalin/LRP2 [17,19,21] and/or transport/clearance across the BBB [17,21]. Additionally, plasmatic IGF1 can be naturally cleaved into des-N (1-3)-IGF-1 and the N-terminal tripeptide, glycine-prolineglutamate (GPE-IGF1) [132,167,168,169].…”

Section: Igf1-r and Pip3: The Common Culpritmentioning

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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Blockade of the insulin-like growth factor I receptor in the choroid plexus originates Alzheimer's-like neuropathology in rodents: New cues into the human disease?

Cited by 126 publications

References 58 publications

Choroid Plexus Megalin Is Involved in Neuroprotection by Serum Insulin-Like Growth Factor I

Choroid Plexus Megalin Is Involved in Neuroprotection by Serum Insulin-Like Growth Factor I

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?

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