Loss of serum IGF-I input to the brain as an early biomarker of disease onset in Alzheimer mice

A Trueba-Sáiz,C Cavada,J Fortea Ormaechea,I Torres-Aleman,A Nuñez,A M Fernandez,T Leon,T Del Ser,A Lleó,D A González

doi:10.1038/tp.2013.102

Abstract

Circulating insulin-like growth factor I (IGF-I) enters the brain and promotes clearance of amyloid peptides known to accumulate in Alzheimer's disease (AD) brains. Both patients and mouse models of AD show decreased level of circulating IGF-I enter the brain as evidenced by a lower ratio of cerebrospinal fluid/plasma IGF-I. Importantly, in presymptomatic AD mice this reduction is already manifested as a decreased brain input of serum IGF-I in response to environmental enrichment. To explore a potential diagnostic use of this early loss of IGF-I input, we monitored electrocorticogram (ECG) responses to systemic IGF-I in mice. Whereas control mice showed enhanced ECG activity after IGF-I, presymptomatic AD mice showed blunted ECG responses. Because nonhuman primates showed identically enhanced electroencephalogram (EEG) activity in response to systemic IGF-I, loss of the EEG signature of serum IGF-I may be exploited as a disease biomarker in AD patients.

Highlights

IntroductionDecades of fruitless search for effective therapies has led to the suggestion that treatment is started too late in the course of the disease to be able to modify it
Alzheimer's disease (AD) is a major public health concern worldwide
We first corroborated that the cerebrospinal fluid (CSF)/plasma ratio of insulin-like growth factor I (IGF-I) is reduced in AD patients as compared with age-matched controls (Figure 1a and Supplementary Table 1)

Summary

Introduction

Decades of fruitless search for effective therapies has led to the suggestion that treatment is started too late in the course of the disease to be able to modify it This is because available diagnostic tools, mostly relying on clinical scales in common practice, can only detect the disease when pathology is already very advanced. The recent guidelines of the US National Institute on Aging and the US Alzheimer’s Association provide a conceptual framework for defining the stages of preclinical AD in which staging requires a combination of biomarkers In this regard, proteomic/genomic signatures in AD patients have already been described,[3,4,5] none have yet reached common practice. There is an unmet need to better define the multidimensional risk in preclinical AD and develop accurate prediction models in order to decide those who should or should not receive the treatment.[6]

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