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

Estibaliz González de San Román,Lydia Giménez-Llort,Alberto Llorente-Ovejero,Rafael Rodríguez-Puertas,Jonatan Martínez-Gardeazabal,Iván Manuel,Marta Moreno-Rodríguez

doi:10.3390/ijms222212256

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 βAPPSwe, PS1M146V, and tauP301L 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 Gi/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.

Highlights

The progressive and irreversible deterioration of cognitive functions present in Alzheimer’s disease (AD) include a chronic neurodegeneration characterized by pathological hallmarks including the loss of synapses, the intracellular neurofibrillary tangles (NFT) [1], and extracellular neuritic plaques [2,3]
AD can be classified into sporadic AD, which accounts for the majority of the cases, and familial early-onset form, accounting for 1–5% of all cases, in which mutations of genes, for example, amyloid β precursor protein (APP) [5], and presenilin-1 and -2 have been suggested to underlie the development of the disease [6,7,8,9]
Assayimmunofluorescent in 3xTg-AD Mice Brain. Sections These results are compared to the anatomical distribution patterns of the lipid distribution in the brain of 3xTg-AD

Summary

Introduction

The progressive and irreversible deterioration of cognitive functions present in Alzheimer’s disease (AD) include a chronic neurodegeneration characterized by pathological hallmarks including the loss of synapses, the intracellular neurofibrillary tangles (NFT) (mostly composed by hyperphosphorylated tau protein) [1], and extracellular neuritic plaques (enriched in Aβ) [2,3]. AD often has comorbidities with other severe human diseases, for example, type 2 diabetes. AD can be classified into sporadic AD, which accounts for the majority of the cases, and familial early-onset form, accounting for 1–5% of all cases, in which mutations of genes, for example, amyloid β precursor protein (APP) [5], and presenilin-1 and -2 have been suggested to underlie the development of the disease [6,7,8,9]. The AD is a complex neurodegenerative disease specific to humans involving multiple factors, such as inflammation [13]. Some animal models have been developed and must be compared to AD patients for their validation. The translational research based on “omics” technologies (including lipidomics) are increasing our knowledge of AD for the identification of early AD biomarkers [14]

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Conclusion