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 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.

Brain areas lipidomics in female transgenic mouse model of Alzheimer's disease

“…In general, the AM is difficult to isolate, so only one work was found, in which a detection of altered lipids in AD was performed. However, its results did not corroborate our findings, probably due to the use of a different mouse model, where only males were included, and at a later stage of the disease, where they already had cognitive impairment 54 .…”

Cannabinoid Receptors and Glial Response Following a Basal Forebrain Cholinergic Lesion

“…Together, these results suggest that, in areas where we have determined that microglia immunoreactivity increased following the lesion, the expected increase in the coupling to G i/0 -proteins evoked by HU308 related to microglial CB 2 was not observed. At the minimum concentration required for these experiments (10 μM), 20 , 54 − 56 the coupling to G i/0 -proteins evoked by HU308 seems to correspond mainly to the CB 1 receptor subtype. This is in line with a previous study also using SR141716A and HU308, which reports that WIN55,212-2, a CB 1 /CB 2 receptor agonist, ameliorated disease progression in a mouse model of MS, exerting CB 1 -mediated anti-inflammatory effects 57 and another study indicating that, in the 5xFAD mice model of AD, CB 1 blockade exacerbated inflammation.…”

“…Briefly, tissue sections mounted on slices were first immersed in copling jars for preincubation and later incubated in the presence of [ 35 S]­GTPγS. CB 1 /CB 2 receptor-mediated coupling to G i/0 -proteins was determined with CP55,940 (10 μM) or HU308 (10 μM) agonists, which was determined in previous studies as the optimal concentration for these type of experiments. ,− Although many neurotransmitter receptors bind agonists with high affinity ( K d ) in the nanomolar range, micromolar concentrations of the same agonists are required to elicit a functional effect and such is the case of the [ 35 S]­GTPγS binding assays. Basal coupling to G i/0 -proteins for each brain area was determined in the absence of agonists.…”

“…18 The regulation of neurotransmission under neurodegenerative conditions modulates eCB signaling, but the contribution of the two main cannabinoid receptors, CB 1 and CB 2 , remains to be elucidated. There is evidence about the involvement of CB 1 cannabinoid receptor in both patients and animal models of AD, 19,20 but the role of the other main cannabinoid receptor, CB 2 , is not yet well understood.…”

Roles of Fatty Acids in Microglial Polarization: Evidence from In Vitro and In Vivo Studies on Neurodegenerative Diseases

“…Our understanding of AD is also growing due to translational research based on "omics" tools, notably lipidomics, which is helping to identify early AD biomarkers. In this regard, the control of neurolipid-mediated signaling, which entails comprehension of the integration of structural, energetic, and signaling functions mediated by lipid molecules in AD patients, may aid in developing efficient therapy approaches for NDs [98].…”