Specific Phospholipid Modulation by Muscarinic Signaling in a Rat Lesion Model of Alzheimer’s Disease

Llorente-Ovejero, Alberto; Martínez‐Gardeazabal, Jonatan; Moreno‐Rodríguez, Marta; Lombardero, Laura; Román, Estíbaliz González de San; Manuel, Iván; Rodrı́guez-Puertas, Rafael

doi:10.1021/acschemneuro.1c00169

Cited by 11 publications

(15 citation statements)

References 82 publications

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“…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), ,− 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 and another study indicating that, in the 5xFAD mice model of AD, CB 1 blockade exacerbated inflammation …”

Section: Resultsmentioning

confidence: 88%

“…[ 35 S]GTPγS binding assays upon activation of cannabinoid receptors were assayed in fresh frozen 20 μm sections of rats from both groups, aCSF ( n = 5) and SAP ( n = 5), as previously described . Briefly, tissue sections mounted on slices were first immersed in copling jars for preincubation and later incubated in the presence of [ 35 S]GTPγS.…”

Section: Methodsmentioning

confidence: 99%

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Cannabinoid Receptors and Glial Response Following a Basal Forebrain Cholinergic Lesion

Llorente-Ovejero

Tena

Martínez‐Gardeazabal

et al. 2022

ACS Pharmacol. Transl. Sci.

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The endocannabinoid system modulates learning, memory, and neuroinflammatory processes, playing a key role in neurodegeneration, including Alzheimer’s disease (AD). Previous results in a rat lesion model of AD showed modulation of endocannabinoid receptor activity in the basalo-cortical pathway following a specific lesion of basal forebrain cholinergic neurons (BFCNs), indicating that the glial neuroinflammatory response accompanying the lesion is related to endocannabinoid signaling. In this study, 7 days after the lesion, decreased astrocyte and increased microglia immunoreactivities (GFAP and Iba-1) were observed, indicating microglia-mediated neuroinflammation. Using autoradiographic studies, the density and functional coupling to G-proteins of endocannabinoid receptor subtypes were studied in tissue sections from different brain areas where microglia density increased, using CB1 and CB2 selective agonists and antagonists. In the presence of the specific CB1 receptor antagonist, SR141716A, [3H]CP55,940 binding (receptor density) was completely blocked in a dose-dependent manner, while the selective CB2 receptor antagonist, SR144528, inhibited binding to 25%, at best. [35S]GTPγS autoradiography (receptor coupling to Gi/0-proteins) evoked by CP55,940 (CB1/CB2 agonist) and HU308 (more selective for CB2) was abolished by SR141716A in all areas, while SR144528 blocked up to 51.8% of the coupling to Gi/0-proteins evoked by CP55,940 restricted to the nucleus basalis magnocellularis. Together, these results demonstrate that there are increased microglia and decreased astrocyte immunoreactivities 1 week after a specific deletion of BFCNs, which projects to cortical areas, where the CB1 receptor coupling to Gi/0-proteins is upregulated. However, at the lesion site, the area with the highest neuroinflammatory response, there is also a limited contribution of CB2.

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Section: Resultsmentioning

confidence: 88%

Section: Methodsmentioning

confidence: 99%

Cannabinoid Receptors and Glial Response Following a Basal Forebrain Cholinergic Lesion

Llorente-Ovejero

Tena

Martínez‐Gardeazabal

et al. 2022

ACS Pharmacol. Transl. Sci.

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“…Neuronal dysfunction in the denervated cortical region mediates degeneration of the basal forebrain cholinergic nucleus, leading to cognitive decline [ 75 ]. The loss of BFCNs can lead to impaired cholinergic neurotransmission, abnormal synaptic function and changes in structural lipid metabolism [ 76 ]. Cholinergic circuits project from the basal forebrain centers to the cerebral cortex and hippocampus [ 36 ].…”

Section: Ad Relation To the Cholinergic Systemmentioning

confidence: 99%

Role of Cholinergic Signaling in Alzheimer’s Disease

et al. 2022

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Acetylcholine, a neurotransmitter secreted by cholinergic neurons, is involved in signal transduction related to memory and learning ability. Alzheimer’s disease (AD), a progressive and commonly diagnosed neurodegenerative disease, is characterized by memory and cognitive decline and behavioral disorders. The pathogenesis of AD is complex and remains unclear, being affected by various factors. The cholinergic hypothesis is the earliest theory about the pathogenesis of AD. Cholinergic atrophy and cognitive decline are accelerated in age-related neurodegenerative diseases such as AD. In addition, abnormal central cholinergic changes can also induce abnormal phosphorylation of ttau protein, nerve cell inflammation, cell apoptosis, and other pathological phenomena, but the exact mechanism of action is still unclear. Due to the complex and unclear pathogenesis, effective methods to prevent and treat AD are unavailable, and research to explore novel therapeutic drugs is various and active in the world. This review summaries the role of cholinergic signaling and the correlation between the cholinergic signaling pathway with other risk factors in AD and provides the latest research about the efficient therapeutic drugs and treatment of AD.

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“…Furthermore, we have recently demonstrated, in a rat lesion model of basal forebrain cholinergic neurons that shows learning and memory impairment, the specific regulation of phospholipids which is controlled by muscarinic receptor signaling [30]. Lipid molecules dynamics, finely tuned by neurotransmitter systems, may play pivotal roles in AD development.…”

Section: Introductionmentioning

confidence: 99%

“…As mentioned above, the study of brain lipids by lipidomic techniques, together with the analysis of neurolipid-based signaling has emerged with important neuromodulatory properties on different neurotransmitter systems in AD [30,40]. The main neurolipid systems identified so far are the endocannabinoid (eCB), and the lysophospholipid signaling systems, including the lysophosphatidic acid (LPA) and the sphingosine 1-phosphate (S1P) [41][42][43].…”

Section: Introductionmentioning

confidence: 99%

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

Román

Llorente-Ovejero

Martínez‐Gardeazabal

et al. 2021

IJMS

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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.

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Specific Phospholipid Modulation by Muscarinic Signaling in a Rat Lesion Model of Alzheimer’s Disease

Cited by 11 publications

References 82 publications

Cannabinoid Receptors and Glial Response Following a Basal Forebrain Cholinergic Lesion

Cannabinoid Receptors and Glial Response Following a Basal Forebrain Cholinergic Lesion

Role of Cholinergic Signaling in Alzheimer’s Disease

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

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