Phenotype analysis of male transgenic mice overexpressing mutant IGFBP-2 lacking the Cardin–Weintraub sequence motif: Reduced expression of synaptic markers and myelin basic protein in the brain and a lower degree of anxiety-like behaviour

Abstract

Brain growth and function are regulated by insulin-like growth factors I and II (IGF-I and IGF-II) but also by IGF-binding proteins (IGFBPs), including IGFBP-2. In addition to modulating IGF activities, IGFBP-2 interacts with a number of components of the extracellular matrix and cell membrane via a Cardin-Weintraub sequence or heparin binding domain (HBD1). The nature and the signalling elicited by these interactions are not fully understood. Here, we examined transgenic mice (H1d-hBP2) overexpressing a mutant human IGFBP-2 that lacks a specific heparin binding domain (HBD1) known as the Cardin-Weintraub sequence. H1d-hBP2 transgenic mice have the genetic background of FVB mice and are characterized by severe deficits in brain growth throughout their lifetime (p<0.05). In tissue lysates from brain hemispheres of 12-21day old male mice, protein levels of the GTPase dynamin-I were significantly reduced (p<0.01). Weight reductions were also found in distinct brain regions in two different age groups (12 and 80weeks). In the younger group, impaired weights were observed in the hippocampus (-34%; p<0.001), cerebellum (-25%; p<0.0001), olfactory bulb (-31%; p<0.05) and prefrontal cortex (-29%; p<0.05). At an age of 12weeks expression of myelin basic protein was reduced (p<0.01) in H1d-BP-2 mice in the cerebellum but not in the hippocampus. At 80weeks of age, weight reductions were similarly present in the cerebellum (-28%; p<0.001) and hippocampus (-31; p<0.05). When mice were challenged in the elevated plus maze, aged but not younger H1d-hBP2 mice displayed significantly less anxiety-like behaviour, which was also observed in a second transgenic mouse model overexpressing mouse IGFBP-2 lacking HBD1 (H1d-mBP2). These in vivo studies provide, for the first time, evidence for a specific role of IGFBP-2 in brain functions associated with anxiety and risk behaviour. These activities of IGFBP-2 could be mediated by the Cardin-Weintraub/HBD1 sequence and are altered in mice expressing IGFBP-2 lacking the HBD1.

Circulating IGFBP‐2: a novel biomarker for incident dementia

“…There is limited published data on the relationship between IGFBP‐2 and structural brain measures. As mentioned, elevated plasma IGFBP‐2 levels have been linked with lower hippocampal volumes, while in transgenic mouse models, overexpression of IGFBP‐2 was noted to be associated with lower total brain weight, as well as reduced hippocampal, prefrontal cortical, and cerebellar weights . Baseline CSF IGFBP‐2 levels have also been longitudinally associated with atrophy in nonhippocampal regions including the parahippocampus, entorhinal cortex as well as inferior and superior temporal lobes …”

Blood-Derived Plasma Protein Biomarkers for Alzheimer’s Disease in Han Chinese

“…IGFBP-2 can influence DNA synthesis, cell proliferation and death, as well as glucose and amino acid uptake in cells by inhibiting IGF functions (Jones and Clemmons, 1995; Reyer et al, 2015). Overexpression of IGFBP-2 in mice led to decreased weights of the hippocampus, cerebellum, olfactory bulb, and prefrontal cortex (Schindler et al, 2017). In addition, IGFBP-2 was also reported to significantly increase in the serum of AD participants (Tham et al, 1993; McLimans et al, 2017), which was consistent with our findings.…”

IGFBP-2 Signaling in the Brain: From Brain Development to Higher Order Brain Functions

“…It has been reported that transgenic mice overexpressing IGFBP-2 lacking a specific heparin-binding domain (HBD-1) showed severe deficits in brain growth throughout their lifetime. In addition, these mice when young (12–21 days) had reduced levels of GTPase dynamin-I, and 12 weeks old mice showed weight reduction in the hippocampus, prefrontal cortex, cerebellum, and olfactory bulb, concomitant with reduced myelin basic protein in the cerebellum (17). These data imply that IGFBP-2 is not only involved in brain development but also with information processing and cognition.…”

“…Though IGFBPs share common sequence homology and functions to regulate IGFs actions, individual proteins (IGFBP-1-6) each have their own unique properties and functions. It has been suggested that overexpression of IGFBPs could be a good model to elucidate the physiological functions of individual IGFBPs (17, 18). IGFBP-2 is most abundant in the CSF (19) and highly expressed in the developing brain.…”