Type-1 cannabinoid receptor activity during Alzheimer's disease progression

The activity of CB1 cannabinoid receptors was studied in postmortem brain samples of Alzheimer's disease (AD) patients during clinical deterioration. CB1 activity was higher at earlier AD stages in limited hippocampal areas and internal layers of frontal cortex, but a decrease was observed at the advanced stages. The pattern of modification appears to indicate initial hyperactivity of the endocannabinoid system in brain areas that lack classical histopathological markers at earlier stages of AD, indicating an attempt to compensate for the initial synaptic impairment, which is then surpassed by disease progression. These results suggest that initial CB1 stimulation might have therapeutic relevance

Imaging mass spectrometry (IMS) of cortical lipids from preclinical to severe stages of Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease affecting millions of patients worldwide. Previous studies have demonstrated alterations in the lipid composition of lipid extracts from plasma and brain samples of AD patients. However, there is no consensus regarding the qualitative and quantitative changes of lipids in brains from AD patients. In addition, the recent developments in imaging mass spectrometry methods are leading to a new stage in the in situ analysis of lipid species in brain tissue slices from human postmortem samples. The present study uses the matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS), permitting the direct anatomical analysis of lipids in postmortem brain sections from AD patients, which are compared with the intensity of the lipid signal in samples from matched subjects with no neurological diseases. The frontal cortex samples from AD patients were classified in three groups based on Braak's histochemical criteria, ranging from non-cognitively impaired patients to those severely affected. The main results indicate a depletion of different sulfatide lipid species from the earliest stages of the disease in both white and gray matter areas of the frontal cortex. Therefore, the decrease in sulfatides in cortical areas could be considered as a marker of the disease, but may also indicate neurochemical modifications related to the pathogenesis of the disease

Neurolipid systems: A new target for the treatment of dementia

Neurolipids comprise a diverse class of bioactive lipids that include molecules capable of activating G protein-coupled receptors, thereby inducing systemic effects that contribute to the maintenance of homeostasis. Dementia, a non-specific brain disorder characterized by a common set of signs and symptoms, usually arises subsequent to brain injuries or diseases and is often associated with the aging process. Individuals affected by dementia suffer from the disruption of several neurotransmitter and neuromodulatory systems, among which neurolipids play an important role, including the endocannabinoid, lysophosphatidic acid and sphingosine 1-phosphate systems. In this review, we present an overview of the most recent and pertinent findings regarding the involvement of these neurolipidic systems in dementia, including data from a wide range of both in vitro and in vivo experiments as well as clinical trials.This work was supported by grants from Basque Government IT1454-22 to the ‘Neurochemistry and Neurodegeneration’ consolidated research group and by Instituto de Salud Carlos III through the project ‘PI20/00153’ (co-funded by European Regional Development Fund ‘A way to make Europe’) and by BIOEF project BIO22/ALZ/010 funded by Eitb Maratoia

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

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.This research was funded by the regional Basque Government IT975-16 to the “Neurochemistry and Neurodegeneration” consolidated research group and ISCIII Spanish Ministry for Health PI20/00153

Cationic polymerization of β-pinene using B(C6F5)3 as a Lewis acid for the synthesis of tackifiers in pressure sensitive adhesives

β-pinene is a well-known bio-based monomer that can be polymerized via cationic polymerization to give low molecular weight resins that find use commercially as tackifiers. However, the controlled synthesis of these polymers by cationic polymerization is challenging due to the reactivity of commonly used Lewis acid catalysts and the propagating carbocationic species with water. Here, the cationic polymerization of β-pinene under mild conditions using the water stable Lewis acid tris(pentafluorophenyl)borane is demonstrated. It is shown that when combined with a suitable alcohol initiator the molecular weight of the polymer can be tuned while the kinetics are largely controlled by the concentration of tris(pentafluorophenyl)borane. The final poly(β-pinene) is shown to perform well as a tackifier in the formation of pressure sensitive adhesives based on polystyrene-b-polyisoprene-b-polystyrene triblock copolymers.N.B. acknowledges the financial support obtained from the Basque government (PI2017-59). The authors thank for technical and human support provided by SGIker of UPV/EHU and European funding (ERDF and ESF). D.E.M.-T. acknowledges financial support from “Ministerio de Ciencia, Innovación y Universidades” (MCIU), via a “Juan de la Cierva – Incorporación” grant (IJCI-2017-31600).Peer reviewe

Synthesis of macrocyclic poly(glycidyl phenyl ether) with an inverted-dipole microstructure via ring closure of two-arm linear precursors obtained by initiation with t-BuP4/water

Dipolar microstructure is a property related to the orientation of dipole moments along a polymer chain, which is dependent on how asymmetric monomers are oriented (i.e., regio-order). The control over the dipolar microstructure offers the possibility to monitor single-chain behavior in an electric field thus providing important structural and dynamical information. Using broadband dielectric spectroscopy (BDS), in this study, we first demonstrate that the initiation of glycidyl phenyl ether with the t-BuP4 phosphazene base and water leads to the formation of a polyether composed of two symmetric regioregular subchains with an opposite dipole moment orientation. After modification of hydroxyl end groups into alkyne, macrocyclic poly(glycidyl phenyl ether)s with an inverted-dipole microstructure were synthesized via Glaser coupling. The macrocycles obtained using this strategy display a dielectric normal mode relaxation that specifically reflects the fluctuations of the ring diameter. This important characteristic allowed us to evaluate the macrocyclic chain dynamics by BDS resulting in a dipole relaxation of the ring diameter 1.6 times slower compared to the analogous relaxation in the inverted-dipole linear precursor. These results highlight two main points, the power of BDS in the verification of architectural features of polymers having a net dipole moment component along the chain contour, and the potential of inverted-dipole macrocycles in the study of fundamental physical problems in polymer rings.We gratefully acknowledge support from the Spanish Ministry “Ministerio de Ciencia, Innovación y Universidades” (PGC2018-094548-B-I00, MICIU/FEDER, UE), the Basque Government (IT-1175-19 and PIBA 2018-34), and NSF-MRI 0619770 for MALDI-ToF MS investigations.Peer reviewe

Type-1 cannabinoid receptor activity during Alzheimer's disease progression

The activity of CB1 cannabinoid receptors was studied in postmortem brain samples of Alzheimer's disease (AD) patients during clinical deterioration. CB1 activity was higher at earlier AD stages in limited hippocampal areas and internal layers of frontal cortex, but a decrease was observed at the advanced stages. The pattern of modification appears to indicate initial hyperactivity of the endocannabinoid system in brain areas that lack classical histopathological markers at earlier stages of AD, indicating an attempt to compensate for the initial synaptic impairment, which is then surpassed by disease progression. These results suggest that initial CB1 stimulation might have therapeutic relevance

Type-1 cannabinoid receptor activity during Alzheimer's disease progression

The activity of CB1 cannabinoid receptors was studied in postmortem brain samples of Alzheimer's disease (AD) patients during clinical deterioration. CB1 activity was higher at earlier AD stages in limited hippocampal areas and internal layers of frontal cortex, but a decrease was observed at the advanced stages. The pattern of modification appears to indicate initial hyperactivity of the endocannabinoid system in brain areas that lack classical histopathological markers at earlier stages of AD, indicating an attempt to compensate for the initial synaptic impairment, which is then surpassed by disease progression. These results suggest that initial CB1 stimulation might have therapeutic relevance

Imaging mass spectrometry (IMS) of cortical lipids from preclinical to severe stages of Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease affecting millions of patients worldwide. Previous studies have demonstrated alterations in the lipid composition of lipid extracts from plasma and brain samples of AD patients. However, there is no consensus regarding the qualitative and quantitative changes of lipids in brains from AD patients. In addition, the recent developments in imaging mass spectrometry methods are leading to a new stage in the in situ analysis of lipid species in brain tissue slices from human postmortem samples. The present study uses the matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS), permitting the direct anatomical analysis of lipids in postmortem brain sections from AD patients, which are compared with the intensity of the lipid signal in samples from matched subjects with no neurological diseases. The frontal cortex samples from AD patients were classified in three groups based on Braak's histochemical criteria, ranging from non-cognitively impaired patients to those severely affected. The main results indicate a depletion of different sulfatide lipid species from the earliest stages of the disease in both white and gray matter areas of the frontal cortex. Therefore, the decrease in sulfatides in cortical areas could be considered as a marker of the disease, but may also indicate neurochemical modifications related to the pathogenesis of the disease

Reactivity of B(C6F5)3 towards glycidol: The formation of branched cyclic polyglycidol structures

B(C6F5)3 is a strong electrophilic catalyst that promote the ring-opening polymerization of a number of epoxides via the formation of zwitterionic growing chains. Cyclic chains frequently are the major component of the reaction, which makes this synthetic route a viable strategy for the generation of cyclic polyethers in large quantities. We present a systematic study on the bulk and quasi-bulk polymerization of glycidol with B(C6F5)3, including kinetic experiments that evidences an abrupt chain growth at high monomer conversions. Ring fusion and branching mechanisms are invoked to explain such phenomenology. Branched cyclic polyglycidols (bcPG) are the major compounds with Mn up to 8 kg/mol and Ð ∼ 2. The glass transition temperature of bcPG exhibits lower values than that of reference linear PG samples likely associated to the dominating effect of branches.We gratefully acknowledge support from the Spanish Ministry “Ministerio de Ciencia e Innovación” (PID2021-123438NB-I00, MICINN/FEDER, UE), Basque Government (IT-1175-19, IT1566-22 and PIBA 2021-1-0034) and Diputación Foral de Guipúzcoa (RED 2021:ID44).Peer reviewe