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 in vivo two-photon microscopy in superficial cortical layers and ex vivo 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-ß (Aß) 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 Aß. Likewise, the NVC responses to somatosensory stimulation were preserved at all regulatory segments of the microvasculature: penetrating arterioles, precapillary sphincters, and capillaries. Lastly, the Aß plaques did not affect the density of capillary pericytes. Conclusion: Our findings provide direct evidence of preserved microvascular function in the 5xFAD mice and highlight the critical dependence of the experimental outcomes on the choice of preclinical models of AD. We propose that the presence of parenchymal Aß does not warrant BBB and NVC dysfunction and that the generalized view that microvascular impairment is inherent to Aß aggregation may need to be revised.

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. Here, we show how some of the concepts developed in her research can be translated to in vivo 2-photon microscopy (2PM) studies of the BBB. We primarily focus on the methods developed in our laboratory to characterize the paracellular diffusion, adsorptive-mediated transcytosis, and receptor-mediated transcytosis of drug nanocarriers at the microscale, illustrating how 2PM can deepen our understanding of the mechanisms of drug delivery to the brain.

Cost of auditory sharpness: Model-Based estimate of energy use by auditory brainstem "octopus" neurons.

Octopus cells (OCs) of the mammalian auditory brainstem precisely encode timing of fast transient sounds and tone onsets. Sharp temporal fidelity of OCs relies on low resting membrane resistance, which suggests high energy expenditure on maintaining ion gradients across plasma membrane. We provide a model-based estimate of energy consumption in resting and spiking OCs. Our results predict that a resting OC consumes up to 2.6 × 109 ATP molecules (ATPs) per second which remarkably exceeds energy consumption of other CNS neurons. Glucose usage by all OCs in the rat is nevertheless low due to their low number. Major part of the OCs energy use results from the ion mechanisms providing for the low membrane resistance: hyperpolarization-activated mixed cation conductance and low-voltage activated K+-conductance. Spatially ordered synapses-a feature of the OCs allowing them to compensate for asynchrony of the synaptic input-brings only a 12% energy saving to OCs excitability cost. Only 13% of total OC energy used for an AP generation (1.5 × 107 ATPs) is associated with the AP generation in the axon initial segment, 64%-with synaptic currents processing and 23%-with keeping resting potential.