Frontal Cortex Lipid Alterations During the Onset of Alzheimer's Disease.

Background: Although sporadic Alzheimer's disease (AD) is a neurodegenerative disorder of unknown etiology, familial AD is associated with specific gene mutations. A commonality between these forms of AD is that both display multiple pathogenic events including cholinergic and lipid dysregulation. Objective: We aimed to identify the relevant lipids and the activity of their related receptors in the frontal cortex and correlating them with cognition during the progression of AD. Methods: MALDI-mass spectrometry imaging (MSI) and functional autoradiography was used to evaluate the distribution of phospholipids/sphingolipids and the activity of cannabinoid 1 (CB1), sphingosine 1-phosphate 1 (S1P1), and muscarinic M2/M4 receptors in the frontal cortex (FC) of people that come to autopsy with premortem clinical diagnosis of AD, mild cognitive impairment (MCI), and no cognitive impairment (NCI). Results: MALDI-MSI revealed an increase in myelin-related lipids, such as diacylglycerol (DG) 36:1, DG 38:5, and phosphatidic acid (PA) 40:6 in the white matter (WM) in MCI compared to NCI, and a downregulation of WM phosphatidylinositol (PI) 38:4 and PI 38:5 levels in AD compared to NCI. Elevated levels of phosphatidylcholine (PC) 32:1, PC 34:0, and sphingomyelin 38:1 were observed in discrete lipid accumulations in the FC supragranular layers during disease progression. Muscarinic M2/M4 receptor activation in layers V-VI decreased in AD compared to MCI. CB1 receptor activity was upregulated in layers V-VI, while S1P1 was downregulated within WM in AD relative to NCI. Conclusions: FC WM lipidomic alterations are associated with myelin dyshomeostasis in prodromal AD, suggesting WM lipid maintenance as a potential therapeutic target for dementia.

Computational method for designing vaccines applied to virus-like particles (VLPs) as epitope carriers.

Nonenveloped virus-like particles (VLPs) are self-assembled oligomeric structures composed of one or more proteins that originate from diverse viruses. Because these VLPs have similar antigenicity to the parental virus, they are successfully used as vaccines against cognate virus infection. Furthermore, after foreign antigenic sequences are inserted in their protein components (chimVLPs), some VLPs are also amenable to producing vaccines against pathogens other than the virus it originates from (these VLPs are named platform or epitope carrier). Designing chimVLP vaccines is challenging because the immunogenic response must be oriented against a given antigen without altering stimulant properties inherent to the VLP. An important step in this process is choosing the location of the sequence modifications because this must be performed without compromising the assembly and stability of the original VLP. Currently, many immunogenic data and computational tools can help guide the design of chimVLPs, thus reducing experimental costs and work. In this study, we analyze the structure of a novel VLP that originate from an insect virus and describe the putative regions of its three structural proteins amenable to insertion. For this purpose, we employed molecular dynamics (MD) simulations to assess chimVLP stability by comparing mutated and wild-type (WT) VLP protein trajectories. We applied this procedure to design a chimVLP that can serve as a prophylactic vaccine against the SARS-CoV-2 virus. The methodology described in this work is generally applicable for VLP-based vaccine development.

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 protein­coupled receptors, thereby inducing systemic effects that contribute to the maintenance of homeostasis. Dementia, a non­specific 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 1­phosphate 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.