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Modulation of Neurolipid Signaling and Specific Lipid Species in the Triple Transgenic Mouse Model of Alzheimer's Disease.

ABSTRACT: Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in aging populations. Recently, the regulation of neurolipid-mediated signaling and cerebral lipid species was shown in AD patients. The triple transgenic mouse model (3xTg-AD), harboring βAPP_Swe, PS1_M146V, and tau_P301L transgenes, mimics many critical aspects of AD neuropathology and progressively develops neuropathological markers. Thus, in the present study, 3xTg-AD mice have been used to test the involvement of the neurolipid-based signaling by endocannabinoids (eCB), lysophosphatidic acid (LPA), and sphingosine 1-phosphate (S1P) in relation to the lipid deregulation. [³⁵S]GTPγS autoradiography was used in the presence of specific agonists WIN55,212-2, LPA and CYM5442, to measure the activity mediated by CB₁, LPA₁, and S1P₁ G_i/0 coupled receptors, respectively. Consecutive slides were used to analyze the relative intensities of multiple lipid species by MALDI Mass spectrometry imaging (MSI) with microscopic anatomical resolution. The quantitative analysis of the astrocyte population was performed by immunohistochemistry. CB₁ receptor activity was decreased in the amygdala and motor cortex of 3xTg-AD mice, but LPA₁ activity was increased in the corpus callosum, motor cortex, hippocampal CA1 area, and striatum. Conversely, S1P₁ activity was reduced in hippocampal areas. Moreover, the observed modifications on PC, PA, SM, and PI intensities in different brain areas depend on their fatty acid composition, including decrease of polyunsaturated fatty acid (PUFA) phospholipids and increase of species containing saturated fatty acids (SFA). The regulation of some lipid species in specific brain regions together with the modulation of the eCB, LPA, and S1P signaling in 3xTg-AD mice indicate a neuroprotective adaptation to improve neurotransmission, relieve the myelination dysfunction, and to attenuate astrocyte-mediated neuroinflammation. These results could contribute to identify new therapeutic strategies based on the regulation of the lipid signaling in familial AD patients.

SUBMITTER: Gonzalez de San Roman E

PROVIDER: S-EPMC8620566 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Neuronal-glial interactions are critical for brain homeostasis, and disruption of this process may lead to excessive glial activation and inadequate pro-inflammatory responses. Abnormalities in neuronal-glial interactions have been reported in the pathophysiology of Alzheimer's disease (AD), where lithium has been shown to exert neuroprotective effects, including the up-regulation of cytoprotective proteins. In the present study, we characterize by Gene Ontology (GO) the signaling pathways related to neuronal-glial interactions in response to lithium in a triple-transgenic mouse model of AD (3×-TgAD). Mice were treated for 8 months with lithium carbonate (Li) supplemented to chow, using two dose ranges to yield subtherapeutic working concentrations (Li1, 1.0 g/kg; and Li2, 2.0 g/kg of chow), or with standard chow (Li0). The hippocampi were removed and analyzed by proteomics. A neuronal-glial interaction network was created by a systematic literature search, and the selected genes were submitted to STRING, a functional network to analyze protein interactions. Proteomics data and neuronal-glial interactomes were compared by GO using ClueGo (Cytoscape plugin) with p ≤ 0.05. The proportional effects of neuron-glia interactions were determined on three GO domains: (i) biological process; (ii) cellular component; and (iii) molecular function. The gene ontology of this enriched network of genes was further stratified according to lithium treatments, with statistically significant effects observed in the Li2 group (as compared to controls) for the GO domains biological process and cellular component. In the former, there was an even distribution of the interactions occurring at the following functions: "positive regulation of protein localization to membrane," "regulation of protein localization to cell periphery," "oligodendrocyte differentiation," and "regulation of protein localization to plasma membrane." In cellular component, interactions were also balanced for "myelin sheath" and "rough endoplasmic reticulum." We conclude that neuronal-glial interactions are implicated in the neuroprotective response mediated by lithium in the hippocampus of AD-transgenic mice. The effect of lithium on homeostatic pathways mediated by the interaction between neurons and glial cells are implicated in membrane permeability, protein synthesis and DNA repair, which may be relevant for the survival of nerve cells amidst AD pathology.

Project description:BackgroundMatrix metallopeptidase 9 (MMP9) has been implicated in a variety of neurological disorders, including Alzheimer's disease (AD), where MMP9 levels are elevated in the brain and cerebrovasculature. Previously our group demonstrated apolipoprotein E4 (apoE4) was less efficient in regulating MMP9 activity in the brain than other apoE isoforms, and that MMP9 inhibition facilitated beta-amyloid (Aβ) elimination across the blood-brain barrier (BBB) METHODS: In the current studies, we evaluated the impact of MMP9 modulation on Aβ disposition and neurobehavior in AD using two approaches, (1) pharmacological inhibition of MMP9 with SB-3CT in apoE4 x AD (E4FAD) mice, and (2) gene deletion of MMP9 in AD mice (MMP9KO/5xFAD) RESULTS: Treatment with the MMP9 inhibitor SB-3CT in E4FAD mice led to reduced anxiety compared to placebo using the elevated plus maze. Deletion of the MMP9 gene in 5xFAD mice also reduced anxiety using the open field test, in addition to improving sociability and social recognition memory, particularly in male mice, as assessed through the three-chamber task, indicating certain behavioral alterations in AD may be mediated by MMP9. However, neither pharmacological inhibition of MMP9 or gene deletion of MMP9 affected spatial learning or memory in the AD animals, as determined through the radial arm water maze. Moreover, the effect of MMP9 modulation on AD neurobehavior was not due to changes in Aβ disposition, as both brain and plasma Aβ levels were unchanged in the SB-3CT-treated E4FAD animals and MMP9KO/AD mice compared to their respective controls.ConclusionsIn total, while MMP9 inhibition did improve specific neurobehavioral deficits associated with AD, such as anxiety and social recognition memory, modulation of MMP9 did not alter spatial learning and memory or Aβ tissue levels in AD animals. While targeting MMP9 may represent a therapeutic strategy to mitigate aspects of neurobehavioral decline in AD, further work is necessary to understand the nature of the relationship between MMP9 activity and neurological dysfunction.

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Modulation of Neurolipid Signaling and Specific Lipid Species in the Triple Transgenic Mouse Model of Alzheimer's Disease.

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