ICAM5 as a Novel Target for Treating Cognitive Impairment in Fragile X Syndrome

Abstract

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, resulted from the silencing of the Fmr1 gene and the subsequent loss of fragile X mental retardation protein (FMRP). Spine dysgenesis and cognitive impairment have been extensively characterized in FXS; however, the underlying mechanism remains poorly understood. As an important regulator of spine maturation, intercellular adhesion molecule 5 (ICAM5) mRNA may be one of the targets of FMRP and involved in cognitive impairment in FXS. Here we show that in Fmr1 KO male mice, ICAM5 was excessively expressed during the late developmental stage, and its expression was negatively correlated with the expression of FMRP and positively related with the morphological abnormalities of dendritic spines. While in vitro reduction of ICAM5 normalized dendritic spine abnormalities in Fmr1 KO neurons, and in vivo knockdown of ICAM5 in the dentate gyrus rescued the impaired spatial and fear memory and anxiety-like behaviors in Fmr1 KO mice, through both granule cell and mossy cell with a relative rate of 1.32 Ϯ 0.15. Furthermore, biochemical analyses showed direct binding of FMRP with ICAM5 mRNA, to the coding sequence of ICAM5 mRNA. Together, our study suggests that ICAM5 is one of the targets of FMRP and is implicated in the molecular pathogenesis of FXS. ICAM5 could be a therapeutic target for treating cognitive impairment in FXS.

Combined DiI and Antibody Labeling Reveals Complex Dysgenesis of Hippocampal Dendritic Spines in a Mouse Model of Fragile X Syndrome

“…Concomitant to an overabundance of thin and branched spines, we detected a decreased abundance of mushroom spines that also displayed smaller heads than WT, a finding in agreement with reports by others [ 46 , 47 , 51 ]. Mushroom spines form strong synapses, as indicated by the correlation of head dimensions with higher synaptic strength and AMPA receptor content [ 81 ].…”

“…Early studies in FXS patients indicated an overabundance of spines [ 44 ], however, analysis of Fmr1 KO mice has produced conflicting results, in particular in the hippocampal region [ 45 ]. In the mature (>60 PND) hippocampus of Fmr1 KO mice, either an increased density of dendritic protrusions [ 46 , 47 ], normal density [ 48 ], or subregion-specific differences were noted compared to WT [ 49 ].…”

Identification of FMRP target mRNAs in the developmental brain: FMRP might coordinate Ras/MAPK, Wnt/β-catenin, and mTOR signaling during corticogenesis

“…[64][65][66][67]. For example, a subset of FMRP target genes including Icam5 (intercellular adhesion molecule 5) [68], Gsk3β (glycogen synthase kinase 3 beta) [50] and glutamate receptor subunits [69] have shown increased protein levels in Fmr1 KO mice. In the present study, however, protein levels of Nf1, Ctnnb1, and mTOR were normal in the Fmr1 KO neocortex, which is similar to previous results regarding other FMRP target genes such as Psd-95 (also known as Dlg4, discs large MAGUK scaffold protein 4) [70], Snap25 (synaptosome associated protein 25) [71] and Cyfip1(cytoplasmic FMR1 interacting protein) [72].…”

Photoaffinity Probes for the Identification of Sequence-Specific Glycosaminoglycan-Binding Proteins

“…Intercellular adhesion molecule 5 (Icam5) and neuroligin-1 (Nlgn1) are cell adhesion molecules linked to neuropsychiatric disorders, including autism, and they play important roles in synapse development and function. [35][36][37] The neuronal pentraxin receptor (Nptxr) is involved in synapse organization and is a potential biomarker of Alzheimer's disease progression. 38,39 Plexin-A4, Nlgn1, Icam5, and Nptxr were independently validated by ELISA, and all showed robust and specific binding to CS-E-, but not CS-C-enriched, polysaccharides ( Figure 4F).…”

“…Our findings suggest a new potential role for CS-E in the regulation of Sema3A/plexin-A4 complexes and semaphorin signaling. Intercellular adhesion molecule 5 (Icam5) and neuroligin-1 (Nlgn1) are cell adhesion molecules linked to neuropsychiatric disorders, including autism, and they play important roles in synapse development and function. − The neuronal pentraxin receptor (Nptxr) is involved in synapse organization and is a potential biomarker of Alzheimer’s disease progression. , Plexin-A4, Nlgn1, Icam5, and Nptxr were independently validated by ELISA, and all showed robust and specific binding to CS-E-, but not CS-C-enriched, polysaccharides (Figure F). Together, these results demonstrate the ability of our GAG photo-cross-linking probes to selectively capture and identify novel GAG-BPs.…”