Neurosci Lett. spatial memory deficits by remyelination, which suggested that myelin injury was involved in spatial memory deficits and remyelination may be a potential therapeutic strategy in early stage of AD or mild cognitive impairments. strong class=”kwd-title” Keywords: 5XFAD mice, Alzheimer’s disease, LINGO\1 antibody, myelin injury, remyelination, spatial memory 1.?INTRODUCTION There is multilevel evidence indicating myelin impairments in Alzheimer’s disease (AD). The number of oligodendrocytes (OLGs) and oligodendrocyte progenitor cells (OPCs), which generate myelin, is reduced significantly in both cortex of APP/PS1 double\transgenic mice and humans.1 The lipid component of myelin in white matter is reduced,2 with changed lipid profile in AD patients.3, 4 The proteins of myelin in regions of cortex and subcortex including myelin basic protein (MBP), 2,3\cyclic nucleotide 3\phosphodiesterase, and proteolipid protein are also decreased significantly.5, 6, 7, 8 The concentrations are found to be higher in cerebrospinal fluid, including ceramide,9 MBP,10 and the antibodies of MBP and myelin oligodendrocyte glycoprotein.11, 12, 13 Furthermore, significant loss of myelin integrity has been shown in patients with AD and mild cognitive impairment (MCI) compared to controls measured by diffusion tensor imaging (DTI),14 and this precedes the onset of cognitive impairment in both healthy aging adults and apolipoprotein E (APOE) 4 carriers.15, 16, 17 Recently, it was demonstrated that transgenic AD mice, including triple\transgenic AD mice and APP/PS1 mice, Rabbit Polyclonal to NDUFA9 exhibit significant abnormalities in myelination patterns and in the expression profiles of oligodendrocyte markers at subregions of the entorhinal cortex (ERC) and hippocampus.18, 19 Myelin ensures saltatory conduction of action potentials, which makes it possible to integrate information across spatially distributed neural networks underlying higher cognitive function,20 such as memory. Preliminary clinical evidence has suggested that the decline in memory is associated with demyelination of neural circuits at AD onset, which is reflected by increases in radial diffusivity (DR) of DTI, especially in the direct or secondary connections to the medial temporal lobe structures, such as parahippocampal white matter (WM), the cingulum, the inferior fronto\occipital fasciculus/unciform fasciculus, and the splenium of the corpus callosum.21 However, it was still unknown whether demyelination plays an important role in memory impairment independent of amyloid and tau pathology in AD. LINGO\1 is an attractive target for remyelination in central nervous system (CNS). This protein, selectively expressed on neurons 22, 23 and OLGs 24 in CNS,22 interacts with the SIRT-IN-2 Nogo\66 receptor (NgR) and p75/TROY/TOJ neurotrophic receptor 25 as a negative regulator for OLGs differentiation and myelination, neuronal survival and axonal regeneration.22, 24 Previous studies found that LINGO\1 and its associated proteins were elevated significantly,26 and endogenous inhibitors of NgR1 were decreased in SIRT-IN-2 hippocampus of aged rats with impaired memory significantly.27 And some researches have shown that LINGO\1 antagonists increase the expression and phosphorylation status of Fyn and decrease the amount of activated RhoA\GTP, thereby promoting differentiation and myelination.24, 28 Based on this evidence, a human monoclonal antibody directed against LINGO\1 (BIIB033) has been used in subjects with relapsing forms of multiple sclerosis (MS) and acute optic neuritis to enhance CNS remyelination. SIRT-IN-2 In this study, we tested the hypothesis that demyelination might be involved in memorial impairment in 5XFAD SIRT-IN-2 mice at early stage of AD. It was shown that myelin injury is an early event in 5XFAD mice prior to emergence of deposition of A and involved in spatial memory deficits, while remyelination with LINGO\1 antibody could attenuate spatial memory deficits. 2.?METHODS 2.1. Transgenic and wild mice 5XFAD mice co\express human APP and presenilin 1 with five familial AD mutations (APP K670N/M671L + I716V + V717I and PS1 M146L + L286V) were obtained from Jackson Laboratories.29 The 5XFAD mice were backcrossed for five generations on the C57BL6/J genetic background in Fujian Medical College. The mice were genotyped using polymerase chain reaction and gel electrophoresis. Only male mice were used for the follow experiments. The experiments used one\month\old and three\month\old male 5XFAD mice, along with age\matched wild\type C57BL6/J mice. All mice were housed in standard 12\h lightCdark cycle (lights on at 7:00 am) with free access to food and water, maintained in.