Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Dec 3;3(12):e330.
doi: 10.1038/tp.2013.102.

Loss of Serum IGF-I Input to the Brain as an Early Biomarker of Disease Onset in Alzheimer Mice

Affiliations
Free PMC article

Loss of Serum IGF-I Input to the Brain as an Early Biomarker of Disease Onset in Alzheimer Mice

A Trueba-Sáiz et al. Transl Psychiatry. .
Free PMC article

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.

Figures

Figure 1
Figure 1
Evidence of reduced serum insulin-like growth factor I (IGF-I) input in Alzheimer's disease (AD). (a) The cerebrospinal fluid (CSF)/serum IGF-I ratio is significantly reduced in Alzheimer patients (n=35); **P<0.01 vs age-matched controls (n=10). (b) The CSF/serum IGF-I ratio is also decreased in young APP (n=6) and APP/PS1 AD-like mice (n=17). WT: age-matched wild-type controls (n=10). Serum IGF-I and CSF were collected from the same individuals to calculate ratios (F=8.538, *P<0.05 and ***P<0.001 vs WT). (c) Phosphorylation of the hippocampal IGF-I receptor in response to environmental enrichment is reduced in AD mice. Both single (APP) and double-mutant (APP/PS1) mice showed reduced IGF-I receptor activity as compared with controls (n=72). After immunoprecipitation with anti-IGF-IR (IGF-I receptor), membranes were blotted with anti-pTyr antibody (4G10, upper blot), stripped and re-blotted with anti-IGF-IR (lower blot) to normalize for total load. Number of animals is indicated on the bars. White bars are animals housed under standard conditions and filled bars are enriched animals (F=15.64, *P<0.05 and ***P<0.001 vs WT). (d) Soluble amyloid (Aβ) reduces in a dose-dependent manner the amount of biotin-labeled IGF-I accumulated by cultured brain endothelial cells (n=3–4; F=10.95, *P<0.05 and ***P<0.001).
Figure 2
Figure 2
Electrocorticogram (ECG) signature of systemic insulin-like growth factor I (IGF-I) in control animals is strongly attenuated in Alzheimer's disease (AD) mice. Intraperitoneal administration of IGF-I in anesthetized animals induces a pronounced increase of α-, β- and θ-band frequencies in the ECG of wild-type (WT) mice (n= 14) as compared with WT injected with saline (n=9), whereas no changes are seen in APP/PS1 mice (n=7) and in presymptomatic APP mice (n=7).
Figure 3
Figure 3
Loss of electrocorticogram (ECG) signature in Alzheimer's disease (AD) mice. Insulin-like growth factor I (IGF-I) induces significant increases in α, β and θ ECG frequency bands and a decrease in δ-wave in control animals. In contrast, both double- and single-mutant AD mice showed no changes. Average changes in ECG bands from 20 to 60 min after IGF-I injection were compared with average baseline levels (paired t-test: **P<0.01, ***P<0.001 vs baseline).
Figure 4
Figure 4
Changes elicited by systemic insulin-like growth factor I (IGF-I) in the electroencephalogram (EEG) activity of anesthetized macaque monkeys. Increased α, β and θ EEG frequency bands are elicited in macaques (n=9) after systemic injection of IGF-I. Note that the response is identical to that seen in wild-type mice but slightly faster because IGF-I was administered intravenously.

Similar articles

See all similar articles

Cited by 23 articles

See all "Cited by" articles

References

    1. Sinha G. European scientists push spinal taps for Alzheimer diagnosis. Nat Med. 2006;12:156. - PubMed
    1. Perrin RJ, Fagan AM, Holtzman DM. Multimodal techniques for diagnosis and prognosis of Alzheimer's disease. Nature. 2009;461:916–922. - PMC - PubMed
    1. Ray S, Britschgi M, Herbert C, Takeda-Uchimura Y, Boxer A, Blennow K, et al. Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins. Nat Med. 2007;13:1359–1362. - PubMed
    1. Fjell AM, Walhovd KB, Fennema-Notestine C, McEvoy LK, Hagler DJ, Holland D, et al. CSF biomarkers in prediction of cerebral and clinical change in mild cognitive impairment and Alzheimer's disease. J Neurosci. 2010;30:2088–2101. - PMC - PubMed
    1. Villemagne VL, Perez KA, Pike KE, Kok WM, Rowe CC, White AR, et al. Blood-borne amyloid-{beta} dimer correlates with clinical markers of Alzheimer's disease. J Neurosci. 2010;30:6315–6322. - PMC - PubMed

Publication types

Substances

Feedback