Misfolding of Amyloid β (Aβ) peptides leads to the formation of extracellular amyloid plaques. Molecular chaperones can facilitate the refolding or degradation of such misfolded proteins. Here, for the first time, we report the unique ability of Lipocalin-type Prostaglandin D synthase (L-PGDS) protein to act as a disaggregase on the pre-formed fibrils of Aβ(1–40), abbreviated as Aβ40, and Aβ(25–35) peptides, in addition to inhibiting the aggregation of Aβ monomers. Furthermore, our proteomics results indicate that L-PGDS can facilitate extraction of several other proteins from the insoluble aggregates extracted from the brain of an Alzheimer’s disease patient. In this study, we have established the mode of binding of L-PGDS with monomeric and fibrillar Aβ using Nuclear Magnetic Resonance (NMR) Spectroscopy, Small Angle X-ray Scattering (SAXS), and Transmission Electron Microscopy (TEM). Our results confirm a direct interaction between L-PGDS and monomeric Aβ40 and Aβ(25–35), thereby inhibiting their spontaneous aggregation. The monomeric unstructured Aβ40 binds to L-PGDS via its C-terminus, while the N-terminus remains free which is observed as a new domain in the L-PGDS-Aβ40 complex model.

The slime of velvet worms (Onychophora) is a strong and fully biodegradable protein material, which upon ejection undergoes a fast liquid-to-solid transition to ensnare prey. However, the molecular mechanisms of slime self-assembly are still not well understood, notably because the primary structures of slime proteins are yet unknown. Combining transcriptomic and proteomic studies, the authors have obtained the complete primary sequences of slime proteins and identified key features for slime self-assembly. The high molecular weight slime proteins contain cysteine residues at the N-and C-termini that mediate the formation of multi-protein complexes via disulfide bonding. Low complexity domains in the N-termini are also identified and their propensity for liquid-liquid phase separation is established, which may play a central role in slime biofabrication. Using solid-state nuclear magnetic resonance, rigid and flexible domains of the slime proteins are mapped to specific peptide domains. The complete sequencing of major slime proteins is an important step toward sustainable fabrication of polymers inspired by the velvet worm slime.

Cerebral preconditioning constitutes the brain's adaptation to lethal ischemia when first exposed to mild doses of a subtoxic stressor. The phenomenon of preconditioning has been largely studied in the heart, and data from in vivo and in vitro models from past 2-3 decades have provided sufficient evidence that similar machinery exists in the brain as well. Since preconditioning results in a transient protective phenotype labeled as ischemic tolerance, it can open many doors in the medical warfare against stroke, a debilitating cerebrovascular disorder that kills or cripples thousands of people worldwide every year. Preconditioning can be induced by a variety of stimuli from hypoxia to pharmacological anesthetics, and each, in turn, induces tolerance by activating a multitude of proteins, enzymes, receptors, transcription factors, and other biomolecules eventually leading to genomic reprogramming. The intracellular signaling pathways and molecular cascades behind preconditioning are extensively being investigated, and several first-rate papers have come out in the last few years centered on the topic of cerebral ischemic tolerance. However, translating the experimental knowledge into the clinical scaffold still evades practicality and faces several challenges. Of the various preconditioning strategies, remote ischemic preconditioning and pharmacological preconditioning appears to be more clinically relevant for the management of ischemic stroke. In this review, we discuss current developments in the field of cerebral preconditioning and then examine the potential of various preconditioning agents to confer neuroprotection in the brain.

Mitochondria play a crucial role in multitude of cellular processes including energy production, calcium signaling, and apoptosis. This remarkable organelle constantly undergoes a complex cycle of fusion and fission, a crucial quality control system for maintaining homeostasis of the cell. Any impairment in this dynamic behavior is linked to a wide range of cellular abnormalities. Consistent with this concept, neuronal apoptosis often emanates in conjunction with rampant mitochondrial fragmentation. The mitochondrial dynamics are tightly regulated by a master mediator called Dynamin related protein 1 (Drp1), which in normal conditions facilitates mitochondrial fission. However, diverse stress conditions induce intensified translocation of cytosolic Drp1 to the mitochondria, contributing excessive fragmentation and concomitant apoptosis. Despite this knowledge, crucial questions such as how fission of the inner and outer mitochondrial membranes is coordinated and how these processes are linked to apoptosis and necrosis remain to be answered. This review focuses on delineating the mechanism of Drp1 activation and explores the pathophysiological importance of dysregulated mitochondrial fission with a special emphasis on ischemic stroke. Further, it also provides a new mechanistic link between ischemia and Drp1-mediated mitochondrial fission.

Drug formulations and suitable methods for their detection play a very crucial role in the development of therapeutics towards degenerative neurological diseases. For diseases such as Alzheimer's disease, magnetic resonance imaging (MRI) is a non-invasive clinical technique suitable for early diagnosis. In this review, we will discuss the different experimental conditions which can push MRI as the technique of choice and the gold standard for early diagnosis of Alzheimer's disease. Here, we describe and compare various techniques for administration of nanoparticles targeted to the brain and suitable formulations of nanoparticles for use as magnetically active therapeutic probes in drug delivery targeting the brain. We explore different physiological pathways involved in the transport of such nanoparticles for successful entry in the brain. In our lab, we have used different formulations of iron oxide nanoparticles (IONPs) and protein nanocages as contrast agents in anatomical MRI of an Alzheimer's disease (AD) brain. We compare these coatings and their benefits to provide the best contrast in addition to biocompatibility properties to be used as sustainable drug-release systems. In the later sections, the contrast enhancement techniques in MRI studies are discussed. Examples of contrast-enhanced imaging using advanced pulse sequences are discussed with the main focus on important studies in the field of neurological diseases. In addition, T1 contrast agents such as gadolinium chelates are compared with the T2 contrast agents mainly made of superparamagnetic inorganic metal nanoparticles.