Preserved blood-brain barrier and neurovascular coupling in female 5xFAD model of Alzheimer's disease.

Introduction: Dysfunction of the cerebral vasculature is considered one of the key components of Alzheimer's disease (AD), but the mechanisms affecting individual brain vessels are poorly understood.

Methods: Here, using two-photon microscopy in superficial cortical layers and imaging across brain regions, we characterized blood-brain barrier (BBB) function and neurovascular coupling (NVC) at the level of individual brain vessels in adult female 5xFAD mice, an aggressive amyloid- (A) model of AD.

Results: We report a lack of abnormal increase in adsorptive-mediated transcytosis of albumin and preserved paracellular barrier for fibrinogen and small molecules despite an extensive load of A.

Blood-Brain Barrier Transport of Transferrin Receptor-Targeted Nanoparticles.

The blood-brain barrier (BBB), built by brain endothelial cells (BECs), is impermeable to biologics. Liposomes and other nanoparticles are good candidates for the delivery of biologics across the BECs, as they can encapsulate numerous molecules of interest in an omnipotent manner. The liposomes need attachment of a targeting molecule, as BECs unfortunately are virtually incapable of uptake of non-targeted liposomes from the circulation.

Shedding Light on the Blood-Brain Barrier Transport with Two-Photon Microscopy In Vivo.

Treatment of brain disorders relies on efficient delivery of therapeutics to the brain, which is hindered by the blood-brain barrier (BBB). The work of Prof. Margareta Hammarlund-Udenaes was instrumental in understanding the principles of drug delivery to the brain and developing new tools to study it.

Post-capillary venules are the key locus for transcytosis-mediated brain delivery of therapeutic nanoparticles.

Effective treatments of neurodegenerative diseases require drugs to be actively transported across the blood-brain barrier (BBB). However, nanoparticle drug carriers explored for this purpose show negligible brain uptake, and the lack of basic understanding of nanoparticle-BBB interactions underlies many translational failures. Here, using two-photon microscopy in mice, we characterize the receptor-mediated transcytosis of nanoparticles at all steps of delivery to the brain in vivo.

Conjugation of Therapeutic PSD-95 Inhibitors to the Cell-Penetrating Peptide Tat Affects Blood-Brain Barrier Adherence, Uptake, and Permeation.

Novel stroke therapies are needed. Inhibition of the interaction between the postsynaptic density-95 (PSD-95)/disc large/ZO-1 (PDZ) domains of PSD-95 and the -methyl-D-aspartate (NMDA) receptor has been suggested as a strategy for relieving neuronal damage. The peptides NR2B9c and -dimer have been designed to hinder this interaction; they are conjugated to the cell-penetrating peptide Tat to facilitate blood-brain barrier (BBB) permeation and neuronal uptake.

Apolipoprotein M-bound sphingosine-1-phosphate regulates blood-brain barrier paracellular permeability and transcytosis.

The blood-brain barrier (BBB) is formed by the endothelial cells lining cerebral microvessels, but how blood-borne signaling molecules influence permeability is incompletely understood. We here examined how the apolipoprotein M (apoM)-bound sphingosine 1-phosphate (S1P) signaling pathway affects the BBB in different categories of cerebral microvessels using ApoM deficient mice (). We used two-photon microscopy to monitor BBB permeability of sodium fluorescein (376 Da), Alexa Fluor (643 Da), and fluorescent albumin (45 kDA).

CaMKII-dependent endoplasmic reticulum fission by whisker stimulation and during cortical spreading depolarization.

Cortical spreading depolarization waves, the cause underlying migraine aura, are also the markers and mechanism of pathology in the acutely injured human brain. Propagation of spreading depolarization wave uniquely depends on the interaction between presynaptic and postsynaptic glutamate N-methyl-d-aspartate receptors (NMDARs). In the normally perfused brain, even a single wave causes a massive depolarization of neurons and glia, which results in transient loss of neuronal function and depression of the ongoing electrocorticographic activity.

PSD-95 uncoupling from NMDA receptors by Tat- N-dimer ameliorates neuronal depolarization in cortical spreading depression.

Cortical spreading depression is associated with activation of NMDA receptors, which interact with the postsynaptic density protein 95 (PSD-95) that binds to nitric oxide synthase (nNOS). Here, we tested whether inhibition of the nNOS/PSD-95/NMDA receptor complex formation by anti-ischemic compound, UCCB01-144 (Tat- N-dimer) ameliorates the persistent effects of cortical spreading depression on cortical function. Using in vivo two-photon microscopy in somatosensory cortex in mice, we show that fluorescently labelled Tat- N-dimer readily crosses blood-brain barrier and accumulates in nerve cells during the first hour after i.

Endogenous IFN-β signaling exerts anti-inflammatory actions in experimentally induced focal cerebral ischemia.

Background: Interferon (IFN)-β exerts anti-inflammatory effects, coupled to remarkable neurological improvements in multiple sclerosis, a neuroinflammatory condition of the central nervous system. Analogously, it has been hypothesized that IFN-β, by limiting inflammation, decreases neuronal death and promotes functional recovery after stroke. However, the core actions of endogenous IFN-β signaling in stroke are unclear.

Potassium-induced structural changes of the endoplasmic reticulum in pyramidal neurons in murine organotypic hippocampal slices.

The endoplasmic reticulum (ER) structure is of central importance for the regulation of cellular anabolism, stress response, and signal transduction. Generally continuous, the ER can temporarily undergo dramatic structural rearrangements resulting in a fragmented appearance. In this study we assess the dynamic nature of ER fission in pyramidal neurons in organotypic hippocampal slice cultures stimulated by depolarizing concentration of potassium (50 mM).

Rapid fragmentation of the endoplasmic reticulum in cortical neurons of the mouse brain in situ following cardiac arrest.

Neuronal endoplasmic reticulum (ER), continuous from soma to dendritic spines, undergoes rapid fragmentation in response to N-methyl-D-aspartate (NMDA) receptor stimulation in hippocampal slices and neuronal primary cultures. Here, we show that ER fragments in the mouse brain following cardiac arrest (CA) induced brain ischemia. The ER structure was assessed in vivo in cortical pyramidal neurons in transgenic mice expressing ER-targeted GFP using two-photon laser scanning microscopy with fluorescence recovery after photobleaching (FRAP).

NMDA receptor stimulation induces reversible fission of the neuronal endoplasmic reticulum.

With few exceptions the endoplasmic reticulum (ER) is considered a continuous system of endomembranes within which proteins and ions can move. We have studied dynamic structural changes of the ER in hippocampal neurons in primary culture and organotypic slices. Fluorescence recovery after photobleaching (FRAP) was used to quantify and model ER structural dynamics.