Age-related cognitive decline, a common component of the brain aging process, is associated with significant impairment in daily functioning and quality of life among geriatric adults. While the complexity of mechanisms underlying cognitive aging are still being elucidated, microbial exposure and the multifactorial inflammatory cascades associated with systemic infections are emerging as potential drivers of neurological senescence. The negative cognitive and neurobiological consequences of a single pathogen-associated inflammatory experience, such as that modeled through treatment with lipopolysaccharide (LPS), are well documented. Yet, the brain aging impacts of repeated, intermittent inflammatory challenges are less well studied. To extend the emerging literature assessing the impact of infection burden on cognitive function among normally aging mice, here, we repeatedly exposed adult mice to intermittent LPS challenges during the aging period. Male 10-month-old C57BL6 mice were systemically administered escalating doses of LPS once every two weeks for 2.5 months. We evaluated cognitive consequences using the non-spatial step-through inhibitory avoidance task, and both spatial working and reference memory versions of the Morris water maze. We also probed several potential mechanisms, including cortical and hippocampal cytokine/chemokine gene expression, as well as hippocampal neuronal function via extracellular field potential recordings. Though there was limited evidence for an ongoing inflammatory state in cortex and hippocampus, we observed impaired learning and memory and a disruption of hippocampal long-term potentiation. These data suggest that a history of intermittent exposure to LPS-induced inflammation is associated with subtle but significantly impaired cognition among normally aging mice. The broader impact of these findings may have important implications for standard of care involving infections in aging individuals or populations at-risk for dementia. 

https://doi.org/10.1101/2022.05.18.491827

Intermittent systemic exposure to lipopolysaccharide-induced inflammation disrupts hippocampal long-term potentiation and impairs cognition in aging male mice

This review examines the roles of HS–proteoglycans (HS–PGs) in general, and, in particular, perlecan and syndecan as representative examples and their interactive ligands, which regulate physiological processes and cellular behavior in health and disease. HS–PGs are essential for the functional properties of tissues both in development and in the extracellular matrix (ECM) remodeling that occurs in response to trauma or disease. HS–PGs interact with a biodiverse range of chemokines, chemokine receptors, protease inhibitors, and growth factors in immune regulation, inflammation, ECM stabilization, and tissue protection. Some cell regulatory proteoglycan receptors are dually modified hybrid HS/CS proteoglycans (betaglycan, CD47). Neurexins provide synaptic stabilization, plasticity, and specificity of interaction, promoting neurotransduction, neurogenesis, and differentiation. Ternary complexes of glypican-1 and Robbo–Slit neuroregulatory proteins direct axonogenesis and neural network formation. Specific neurexin–neuroligin complexes stabilize synaptic interactions and neural activity. Disruption in these interactions leads to neurological deficits in disorders of functional cognitive decline. Interactions with HS–PGs also promote or inhibit tumor development. Thus, HS–PGs have complex and diverse regulatory roles in the physiological processes that regulate cellular behavior and the functional properties of normal and pathological tissues. Specialized HS–PGs, such as the neurexins, pikachurin, and Eyes-shut, provide synaptic stabilization and specificity of neural transduction and also stabilize the axenome primary cilium of phototoreceptors and ribbon synapse interactions with bipolar neurons of retinal neural networks, which are essential in ocular vision. Pikachurin and Eyes–Shut interactions with an α-dystroglycan stabilize the photoreceptor synapse. Novel regulatory roles for HS–PGs controlling cell behavior and tissue function are expected to continue to be uncovered in this fascinating class of proteoglycan.

The Glycosaminoglycan Side Chains and Modular Core Proteins of Heparan Sulphate Proteoglycans and the Varied Ways They Provide Tissue Protection by Regulating Physiological Processes and Cellular Behaviour

Sex differences in neuroimmunoendocrine communication. Involvement on longevity

BACKGROUND: Drug discovery for stroke is challenging as indicated by poor clinical translatability. In contrast, HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors (ie, statins) improve poststroke neurological outcomes. This property requires transport across the blood-brain barrier via an endogenous uptake transporter (ie, Oatp1a4 [organic anion transporting polypeptide 1a4]). Our goal was to study Oatp1a4 as a drug delivery mechanism because the blood-brain barrier cannot be assumed to be completely open for all drugs in ischemic stroke. METHODS: Male Sprague-Dawley rats (200–250 g) were subjected to middle cerebral artery occlusion (90 minutes) followed by reperfusion for up to 7 days. Atorvastatin (20 mg/kg, IV) was administered 2 hours following intraluminal suture removal. Involvement of Oatp-mediated transport was determined using fexofenadine (3.2 mg/kg, IV), a competitive Oatp inhibitor. Oatp1a4 transport activity was measured by in situ brain perfusion. Infarction volumes/brain edema ratios and neuronal nuclei expression were determined using 2,3,5-triphenyltetrazolium chloride–stained brain tissue slices and confocal microscopy, respectively. Poststroke functional outcomes were assessed via neurological deficit scores and rotarod analysis. RESULTS: At 2-hour post–middle cerebral artery occlusion, [3H]atorvastatin uptake was increased in ischemic brain tissue. A single dose of atorvastatin significantly reduced post–middle cerebral artery occlusion infarction volume, decreased brain edema ratio, increased caudoputamen neuronal nuclei expression, and improved functional neurological outcomes. All middle cerebral artery occlusion positive effects of atorvastatin were attenuated by fexofenadine coadministration (ie, an Oatp transport inhibitor). CONCLUSIONS: Our data demonstrate that neuroprotective effects of atorvastatin may require central nervous system delivery by Oatp-mediated transport at the blood-brain barrier, a mechanism that persists despite increased cerebrovascular permeability in ischemic stroke. These novel and translational findings support utility of blood-brain barrier transporters in drug delivery for neuroprotective agents.

Oatp (Organic Anion Transporting Polypeptide)-Mediated Transport: A Mechanism for Atorvastatin Neuroprotection in Stroke

https://doi.org/10.1016/j.ijchp.2022.100356

Antenatal depressive symptoms are strongly predicted by the severity of pre-menstrual syndrome: results of partial least squares analysis

Major depression is a significant medical issue impacting millions of individuals worldwide. Identifying factors contributing to its manifestation has been a subject of intense investigation for decades and several targets have emerged including sex hormones and the immune system. Indeed, an extensive body of literature has demonstrated that sex hormones play a critical role in modulating brain function and impacting mental health, especially among female organisms. Emerging findings also indicate an inflammatory etiology of major depression, revealing new opportunities to supplement, or even supersede, currently available pharmacological interventions in some patient populations. Given the established sex differences in immunity and the profound impact of fluctuations of sex hormone levels on the immune system within the female, interrogating how the endocrine, nervous, and immune systems converge to impact women’s mental health is warranted. Here, we review the impacts of endogenous estrogens as well as exogenously administered estrogen-containing therapies on affect and immunity and discuss these observations in the context of distinct reproductive milestones across the female lifespan. A theoretical framework and important considerations for additional study in regards to mental health and major depression are provided.

/pdf/estrogen-the-peripheral-immune-system-and-major-depression-a-3thfkdj5.pdf

Estrogen, the Peripheral Immune System and Major Depression – A Reproductive Lifespan Perspective

Background: Physical activity is associated with improved brain health and cognition in humans. However, the validity, range, and quality of evidence for the beneficial outcomes linked to exercise in experimental models of vascular dementia (VaD) have not been evaluated. We performed a systematic review and meta-analysis of studies that assessed the effect of exercise intervention on models of VaD to provide an unbiased and comprehensive determination of the cognitive function and brain morphology benefits of exercise. Summary: A systematic search in three databases as well as study design characteristics and experimental data extraction were completed in December 2021. We investigated the effects of exercise on cognitive function and brain-morphology outcomes in VaD models. Twenty-five studies were included for systematic review, while 21 studies were included in the meta-analysis. These studies included seven models of VaD in rats (60%, 15 studies), mice (36%, 9 studies), and pigs (4%, 1 study). None of the included studies used aged animals, and the majority of studies (80%) used only male animals. Key Message: Exercise improves cognition but increased neuro-inflammation in VaD models. Exercise improved cognitive function as well as some markers of brain morphology in models of VaD. However, exercise increased anxiety and neuro-inflammatory signals in VaD models. Further, we observed increased reporting anomalies such as a lack of blinding to group treatment or data analysis and randomization of animals to groups. Our report could help in the appropriate design of experimental studies seeking to investigate the effects of exercise as a non-pharmacological intervention on VaD models with a high translational impact.

The Effects of Physical Activity on Experimental Models of Vascular Dementia: A Systematic Review and Meta-Analysis

Intraluminal monofilament model of middle cerebral artery occlusion (MCAO) is widely adopted for ischemic stroke; and Sprague-Dawley (SD) rats are commonly used rodents for preclinical research. Due to the paucity of information on the appropriate monofilament size for inducing MCAO in SD rats and the importance of including middle-aged models in ischemic stroke studies, we aimed to: (i). determine an appropriate Doccol® monofilament size for middle-aged male SD rats which weighed > 500 g following 24-h transient MCAO survival as well as (ii). demonstrate the optimal Doccol® filament size for middle-aged males (≤ 500 g) and females (273-300 g) while using young adult male SD rats (372-472 g) as control for severity of infarct volume following 7-days post-MCAO. All rats were subjected to 90-min transient MCAO. We show that 0.43 mm Doccol® monofilament size is more appropriate to induce large infarct lesion and optimal functional deficit when compared to 0.45 mm and 0.47 mm at 24 h post-MCAO. Our data on infarct volumes at 7 days post-MCAO as well as the observed weight loss and functional deficits at post-MCAO days 1, 3 and 7 demonstrate that 0.41 mm, 0.37 mm and 0.39 mm are optimal Doccol® filament sizes for middle-aged male (477.3 ± 39.61 g) and female (302.6 ± 26.28 g) as well as young-adult male (362.2 ± 28.38 g) SD rats, respectively. 

/pdf/optimizing-intraluminal-monofilament-model-of-ischemic-3bzhjj1z.pdf

Optimizing intraluminal monofilament model of ischemic stroke in middle-aged Sprague–Dawley rats

Perlecan is a 500 kDa proteoglycan residing in the extracellular matrix of endothelial basement membranes with five distinct protein domains and three heparan sulfate chains. The complex structure of perlecan and the interaction it has with its local environment accounts for its various cellular and tissue-related effects, to include cartilage, bone, neural and cardiac development, angiogenesis, and blood brain barrier stability. As perlecan is a key contributor to extracellular matrix health involved in many tissues and processes throughout the body, dysregulation of perlecan has the potential to contribute to various neurological and musculoskeletal diseases. Here we review key findings associated with perlecan dysregulation in the context of disease. This is a narrative review article examining perlecanâ€™s role in diseases of neural and musucloskeletal pathology and its potential as a therapeutic index. Literature searches were conducted on the PubMed database, and were focused on perlecan’s impact in neurological disease, to include ischemic stroke, Alzheimer’s Disease (AD) and brain arteriovenous malformation (BAVM), as well as musculoskeletal pathology, including Dyssegmental Dysplasia Silverman-Handmaker type (DDSH), Schwartz-Jampel syndrome (SJS), sarcopenia, and osteoarthritis (OA). PRISMA guidelines were utilized in the search and final selection of articles.Increased perlecan levels were associated with sarcopenia, OA, and BAVM, while decreased perlecan was associated with DDSH, and SJS. We also examined the therapeutic potential of perlecan signaling in ischemic stroke, AD, and osteoarthritic animal models. Perlecan experimentally improved outcomes in such models of ischemic stroke and AD, and we found that it may be a promising component of future therapeutics for such pathology. In treating the pathophysiology of sarcopenia, OA, and BAVM, inhibiting the effect of perlecan may be beneficial. As perlecan binds to both Î±-5 integrin and VEGFR2 receptors, tissue specific inhibitors of these proteins warrant further study. In addition, analysis of experimental data revealed promising insight into the potential uses of perlecan domain V as a broad treatment for ischemic stroke and AD. As these diseases have limited therapeutic options, further study into perlecan or its derivatives and its potential to be used as novel therapeutic for these and other diseases should be seriously considered.

/pdf/perlecan-a-review-of-its-role-in-neurologic-and-ctlcowe3.pdf

Perlecan: a review of its role in neurologic and musculoskeletal disease

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Estrogen, the Peripheral Immune System and Major Depression – A Reproductive Lifespan Perspective

The Effects of Physical Activity on Experimental Models of Vascular Dementia: A Systematic Review and Meta-Analysis

Optimizing intraluminal monofilament model of ischemic stroke in middle-aged Sprague–Dawley rats

Perlecan: a review of its role in neurologic and musculoskeletal disease