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1. Disrupted Excitation-Inhibition Balance in Cognitively Normal Individuals at Risk of Alzheimer’s Disease

   https://doi.org/10.3233/JAD-230035  

   Fortel, Igor; Zhan, Liang; Ajilore, Olusola; Wu, Yichao; Mackin, Scott; Leow, Alex (October 2023, Journal of Alzheimer's Disease)

   Background: Sex differences impact Alzheimer’s disease (AD) neuropathology, but cell-to-network level dysfunctions in the prodromal phase are unclear. Alterations in hippocampal excitation-inhibition balance (EIB) have recently been linked to early AD pathology. Objective: Examine how AD risk factors (age, APOE ɛ4, amyloid-β) relate to hippocampal EIB in cognitively normal males and females using connectome-level measures. Methods: Individuals from the OASIS-3 cohort (age 42–95) were studied (N = 437), with a subset aged 65+ undergoing neuropsychological testing (N = 231). Results: In absence of AD risk factors (APOE ɛ4/Aβ+), whole-brain EIB decreases with age more significantly in males than females (p = 0.021, β= –0.007). Regression modeling including APOE ɛ4 allele carriers (Aβ–) yielded a significant positive AGE-by-APOE interaction in the right hippocampus for females only (p = 0.013, β= 0.014), persisting with inclusion of Aβ+ individuals (p = 0.012, β= 0.014). Partial correlation analyses of neuropsychological testing showed significant associations with EIB in females: positive correlations between right hippocampal EIB with categorical fluency and whole-brain EIB with the Trail Making Test (p < 0.05). Conclusions: Sex differences in EIB emerge during normal aging and progresses differently with AD risk. Results suggest APOE ɛ4 disrupts hippocampal balance more than amyloid in females. Increased excitation correlates positively with neuropsychological performance in the female group, suggesting a duality in terms of potential beneficial effects prior to cognitive impairment. This underscores the translational relevance of APOE ɛ4 related hyperexcitation in females, potentially informing therapeutic targets or early interventions to mitigate AD progression in this vulnerable population. 

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2. Hemodynamic Characteristics of a Tortuous Microvessel Using High‐Fidelity Red Blood Cell Resolved Simulations

   https://doi.org/10.1111/micc.12875  

   Hossain, Mir Md Nasim; Hu, Nien‐Wen; Kazempour, Ali; Murfee, Walter L.; Balogh, Peter (July 2024, Microcirculation)

   ABSTRACT ObjectiveTortuous microvessels are characteristic of microvascular remodeling associated with numerous physiological and pathological scenarios. Three‐dimensional (3D) hemodynamics in tortuous microvessels influenced by red blood cells (RBCs), however, are largely unknown, and important questions remain. Is blood viscosity influenced by vessel tortuosity? How do RBC dynamics affect wall shear stress (WSS) patterns and the near‐wall cell‐free layer (CFL) over a range of conditions? The objective of this work was to parameterize hemodynamic characteristics unique to a tortuous microvessel. MethodsRBC‐resolved simulations were performed using an immersed boundary method‐based 3D fluid dynamics solver. A representative tortuous microvessel was selected from a stimulated angiogenic network obtained from imaging of the rat mesentery and digitally reconstructed for the simulations. The representative microvessel was a venule with a diameter of approximately 20 μm. The model assumes a constant diameter along the vessel length and does not consider variations due to endothelial cell shapes or the endothelial surface layer. ResultsMicrovessel tortuosity was observed to increase blood apparent viscosity compared to a straight tube by up to 26%. WSS spatial variations in high curvature regions reached 23.6 dyne/cm²over the vessel cross‐section. The magnitudes of WSS and CFL thickness variations due to tortuosity were strongly influenced by shear rate and negligibly influenced by tube hematocrit levels. ConclusionsNew findings from this work reveal unique tortuosity‐dependent hemodynamic characteristics over a range of conditions. The results provide new thought‐provoking information to better understand the contribution of tortuous vessels in physiological and pathological processes and help improve reduced‐order models. 

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3. Transcriptomic comparison of human and mouse brain microvessels

   https://doi.org/10.1038/s41598-020-69096-7  

   Song, Hannah W.; Foreman, Koji L.; Gastfriend, Benjamin D.; Kuo, John S.; Palecek, Sean P.; Shusta, Eric V. (July 2020, Scientific Reports)

   Abstract The brain vasculature maintains brain homeostasis by tightly regulating ionic, molecular, and cellular transport between the blood and the brain parenchyma. These blood–brain barrier (BBB) properties are impediments to brain drug delivery, and brain vascular dysfunction accompanies many neurological disorders. The molecular constituents of brain microvascular endothelial cells (BMECs) and pericytes, which share a basement membrane and comprise the microvessel structure, remain incompletely characterized, particularly in humans. To improve the molecular database of these cell types, we performed RNA sequencing on brain microvessel preparations isolated from snap-frozen human and mouse tissues by laser capture microdissection (LCM). The resulting transcriptome datasets from LCM microvessels were enriched in known brain endothelial and pericyte markers, and global comparison identified previously unknown microvessel-enriched genes. We used these datasets to identify mouse-human species differences in microvessel-associated gene expression that may have relevance to BBB regulation and drug delivery. Further, by comparison of human LCM microvessel data with existing human BMEC transcriptomic datasets, we identified novel putative markers of human brain pericytes. Together, these data improve the molecular definition of BMECs and brain pericytes, and are a resource for rational development of new brain-penetrant therapeutics and for advancing understanding of brain vascular function and dysfunction. 

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4. Evaluating cell viability, capillary perfusion, and collateral tortuosity in an ex vivo mouse intestine fluidics model

   https://doi.org/10.3389/fbioe.2022.1008481  

   Willi, Caroline E.; Abdelazim, Hanaa; Chappell, John C. (December 2022, Frontiers in Bioengineering and Biotechnology)

   Numerous disease conditions involve the sudden or progressive loss of blood flow. Perfusion restoration is vital for returning affected organs to full health. While a range of clinical interventions can successfully restore flow to downstream tissues, the microvascular responses after a loss-of-flow event can vary over time and may involve substantial microvessel instability. Increased insight into perfusion-mediated capillary stability and access-to-flow is therefore essential for advancing therapeutic reperfusion strategies and improving patient outcomes. To that end, we developed a tissue-based microvascular fluidics model to better understand (i) microvascular stability and access-to-flow over an acute time course post-ischemia, and (ii) collateral flow in vessels neighboring an occlusion site. We utilized murine intestinal tissue regions by catheterizing a feeder artery and introducing perfusate at physiologically comparable flow-rates. The cannulated vessel as well as a portion of the downstream vessels and associated intestinal tissue were cultured while constant perfusion conditions were maintained. An occlusion was introduced in a selected arterial segment, and changes in perfusion within areas receiving varying degrees of collateral flow were observed over time. To observe the microvascular response to perfusion changes, we incorporated (i) tissues harboring cell-reporter constructs, specifically Ng2-DsRed labeling of intestinal pericytes, and (ii) different types of fluorescent perfusates to quantify capillary access-to-flow at discrete time points. In our model, we found that perfusion tracers could enter capillaries within regions downstream of an occlusion upon the initial introduction of perfusion, but at 24 h tissue perfusion was severely decreased. However, live/dead cell discrimination revealed that the tissue overall did not experience significant cell death, including that of microvascular pericytes, even after 48 h. Our findings suggest that altered flow conditions may rapidly initiate cellular responses that reduce capillary access-to-flow, even in the absence of cellular deterioration or hypoxia. Overall, this ex vivo tissue-based microfluidics model may serve as a platform upon which a variety of follow-on studies may be conducted. It will thus enhance our understanding of microvessel stability and access-to-flow during an occlusive event and the role of collateral flow during normal and disrupted perfusion. 

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5. Long-term transverse imaging of the hippocampus with glass microperiscopes

   https://doi.org/10.7554/eLife.75391  

   Redman, William T; Wolcott, Nora S; Montelisciani, Luca; Luna, Gabriel; Marks, Tyler D; Sit, Kevin K; Yu, Che-Hang; Smith, Spencer; Goard, Michael J (July 2022, eLife)

   The hippocampus consists of a stereotyped neuronal circuit repeated along the septal-temporal axis. This transverse circuit contains distinct subfields with stereotyped connectivity that support crucial cognitive processes, including episodic and spatial memory. However, comprehensive measurements across the transverse hippocampal circuit in vivo are intractable with existing techniques. Here, we developed an approach for two-photon imaging of the transverse hippocampal plane in awake mice via implanted glass microperiscopes, allowing optical access to the major hippocampal subfields and to the dendritic arbor of pyramidal neurons. Using this approach, we tracked dendritic morphological dynamics on CA1 apical dendrites and characterized spine turnover. We then used calcium imaging to quantify the prevalence of place and speed cells across subfields. Finally, we measured the anatomical distribution of spatial information, finding a non-uniform distribution of spatial selectivity along the DG-to-CA1 axis. This approach extends the existing toolbox for structural and functional measurements of hippocampal circuitry. 

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