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.

Lipids not only constitute the primary component of cellular membranes and contribute to metabolism but also serve as intracellular signaling molecules and bind to specific membrane receptors to control cell proliferation, growth and convey neuroprotection. Over the last several decades, the development of new analytical techniques, such as imaging mass spectrometry (IMS), has contributed to our understanding of their involvement in physiological and pathological conditions. IMS allows researchers to obtain a wide range of information about the spatial distribution and abundance of the different lipid molecules that is crucial to understand brain functions. The primary aim of this study was to map the spatial distribution of different lipid species in the rat central nervous system (CNS) using IMS to find a possible relationship between anatomical localization and physiology. The data obtained were subsequently applied to a model of neurological disease, the 192IgG-saporin lesion model of memory impairment. The results were obtained using a LTQ-Orbitrap XL mass spectrometer in positive and negative ionization modes and analyzed by ImageQuest and MSIReader software. A total of 176 different molecules were recorded based on the specific localization of their intensities. However, only 34 lipid species in negative mode and 51 in positive were assigned to known molecules with an error of 5ppm. These molecules were grouped by different lipid families, resulting in: Phosphatidylcholines (PC): PC (34: 1)+K and PC (32: 0)+K distributed primarily in gray matter, and PC (36: 1)+K and PC (38: 1)+Na distributed in white matter. Phosphatidic acid (PA): PA (38: 3)+K in white matter, and PA (38: 5)+K in gray matter and brain ventricles. Phosphoinositol (PI): PI (18: 0/20: 4)-H in gray matter, and PI (O-30: 1) or PI (P-30: 0)-H in white matter. Phosphatidylserines (PS): PS (34: 1)-H in gray matter, and PS (38: 1)-H in white matter. Sphingomyelin (SM) SM (d18: 1/16: 0)-H in ventricles and SM (d18: 1/18: 0)-H in gray matter. Sulfatides (ST): ST (d18: 1/24: 1)-H in white matter. The specific distribution of different lipids supports their involvement not only in structural and metabolic functions but also as intracellular effectors or specific receptor ligands and/or precursors. Moreover, the specific localization in the CNS described here will enable us to analyze lipid distribution to identify their physiological conditions in rat models of neurodegenerative pathologies, such as Alzheimer's disease. This article is part of a Special Issue entitled: Membrane Lipid Therapy: Drugs Targeting Biomembranes edited by Pablo V. Escribá.

Non-alcoholic steatohepatitis (NASH) is the leading cause of chronic liver injury and the third most common reason for liver transplantations in Western countries. It is unclear so far how different fat sources in Western diets (WD) influence the development of NASH. Our study investigates the impact of non-trans fat (NTF) and corn oil (Corn) as fat source in a WD mouse model of steatohepatitis on disease development and progression. C57BL/6J wildtype (WT) mice were fed “standard” WD (WD-Std), WD-NTF or WD-Corn for 24 weeks. WT animals treated with WD-NTF exhibit distinct features of the metabolic syndrome compared to WD-Std and WD-Corn. This becomes evident by a worsened insulin resistance and elevated serum ALT, cholesterol and triglyceride (TG) levels compared to WD-Corn. Animals fed WD-Corn on the contrary tend to a weakened disease progression in the described parameters. After 24 weeks feeding with WD-NTF and WD-Std, WD-Corn lead to a comparable steatohepatitis initiation by histomorphological changes and immune cell infiltration compared to WD-Std. Immune cell infiltration results in a significant increase in mRNA expression of the pro-inflammatory cytokines IL-6 and TNF-α, which is more pronounced in WD-NTF compared to WD-Std and WD-Corn. Interestingly the fat source has no impact on the composition of accumulating fat within liver tissue as determined by matrix-assisted laser desorption/ionization mass spectrometry imaging of multiple lipid classes. The described effects of different fat sources on the development of steatohepatitis finally resulted in variations in fibrosis development. Animals treated with WD-NTF displayed massive collagen accumulation, whereas WD-Corn even seems to protect from extracellular matrix deposition. Noteworthy, WD-Corn provokes massive histomorphological modifications in epididymal white adipose tissue (eWAT) and severe accumulation of extracellular matrix which are not apparent in WD-Std and WD-NTF treatment. Different fat sources in WD-Std contribute to strong steatohepatitis development in WT mice after 24 weeks treatment. Surprisingly, corn oil provokes histomorphological changes in eWAT tissue. Accordingly, both WD-NTF and WD-Corn appear suitable as alternative dietary treatment to replace “standard” WD-Std as a diet mouse model of steatohepatitis whereas WD-Corn leads to strong changes in eWAT morphology.

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. This article is part of a Special Issue entitled: Membrane Lipid Therapy: Drugs Targeting Biomembranes edited by Pablo V. Escribá.

Autoradiography is used to determine the anatomical distribution of biological molecules in human tissue and experimental animal models. This method is based on the analysis of the specific binding of radiolabeled compounds to locate neurotransmitter receptors or transporters in fresh frozen tissue slices. The anatomical resolution obtained by quantification of the radioligands has allowed the density of receptor proteins to be mapped over the last 40 years. The data yielded by autoradiography identify the receptors at their specific microscopic localization in the tissues and also in their native microenvironment, the intact cell membrane. Furthermore, in functional autoradiography, the effects of small molecules on the activity of G protein-coupled receptors are evaluated. More recently, autoradiography has been combined with membrane microarrays to improve the high-throughput screening of compounds. These technical advances have made autoradiography an essential analytical method for the progress of drug discovery. We include the future prospects and some preliminary results for imaging mass spectrometry (IMS) as a useful new method in pharmacodynamic and pharmacokinetic studies, complementing autoradiographic studies. IMS results could also be presented as density maps of molecules, proteins, and metabolites in tissue sections that can be identified, localized, and quantified, with the advantage of avoiding any labeling of marker molecules. The limitations and future developments of these techniques are discussed here.