Synthesis of human amyloid restricted to liver results in an Alzheimer disease-like neurodegenerative phenotype.

Several lines of study suggest that peripheral metabolism of amyloid beta (Aß) is associated with risk for Alzheimer disease (AD). In blood, greater than 90% of Aß is complexed as an apolipoprotein, raising the possibility of a lipoprotein-mediated axis for AD risk. In this study, we report that genetic modification of C57BL/6J mice engineered to synthesise human Aß only in liver (hepatocyte-specific human amyloid (HSHA) strain) has marked neurodegeneration concomitant with capillary dysfunction, parenchymal extravasation of lipoprotein-Aß, and neurovascular inflammation. Moreover, the HSHA mice showed impaired performance in the passive avoidance test, suggesting impairment in hippocampal-dependent learning. Transmission electron microscopy shows marked neurovascular disruption in HSHA mice. This study provides causal evidence of a lipoprotein-Aß /capillary axis for onset and progression of a neurodegenerative process.

L-arginine and aged garlic extract for the prevention of migraine: a study protocol for a randomised, double-blind, placebo-controlled, phase-II trial (LARGE trial).

BACKGROUND: Migraine is a common and distressing neurological condition characterised by recurrent throbbing headaches, nausea and heightened sensitivity to light and sound. Accumulating evidence suggests that cerebral arteries dilate during migraine, causing distal microvessels to constrict, which could activate nociceptors and cause onset of headache pain. If so, preventing or attenuating chronic microvascular constriction, and promoting a dilatory phenotype, may reduce frequency and/or severity of migraines. The primary aim of the L-Arginine and Aged Garlic Extract (LARGE) trial is to investigate whether oral treatment with dietary nutraceuticals, L-arginine and aged garlic extract (AGE), both systemic vasodilatory agents, will alleviate migraine frequency, duration and severity in adults with chronic frequent episodic migraines. METHODS: The study is a randomised double-blind placebo-controlled phase-II single-site clinical trial conducted in Perth, Australia. The target sample is to recruit 240 participants diagnosed with chronic frequent episodic migraines between 18 and 80 years of age. Participants will be randomised to one of four treatment groups for 14 weeks (placebo induction for 2 weeks, followed by 12 weeks on one of the respective treatment arms): placebo, L-arginine, AGE, or a combination of L-arginine and AGE. The doses of L-arginine and AGE are 1.5 g and 1 g daily, respectively. The primary outcome is to assess migraine response using change in migraine frequency and intensity between baseline and 12 weeks. Secondary outcomes include the impact of L-arginine and/or AGE on photosensitivity, retinal vessel changes, and blood biomarker concentrations of vascular tone, following a 12-week intervention. DISCUSSION: The protocol describes the oral administration of 2 nutraceutical-based interventions as possible prophylactic treatments for chronic frequent episodic migraines, with potential for direct clinical translation of outcomes. Potential limitations of the study include the fixed-dose design of each treatment arm and that in vivo neuroimaging methods, such as magnetic resonance imaging (MRI), will not be conducted to determine putative cerebro-vasodilatory changes to coincide with the outcome measures. Dose-response studies may be indicated. TRIAL REGISTRATION: The trial was retrospectively registered with the Australian New Zealand Clinical Trials Registry ACTRN12621001476820 (Universal Trial Number: U1111-1268-1117) on 04/08/2021. This is protocol version 1, submitted on 25/11/2022.

A highly sensitive LC-MS/MS method for quantitative determination of 7 vitamin D metabolites in mouse brain tissue.

Despite its critical role in neurodevelopment and brain function, vitamin D (vit-D) homeostasis, metabolism, and kinetics within the central nervous system remain largely undetermined. Thus, it is of critical importance to establish an accurate, highly sensitive, and reproducible method to quantitate vit-D in brain tissue. Here, we present a novel liquid chromatography tandem mass spectrometry (LC-MS/MS) method and for the first time, demonstrate detection of seven major vit-D metabolites in brain tissues of C57BL/6J wild-type mice, namely 1,25(OH)2D3, 3-epi-1,25(OH)2D3, 1,25(OH)2D2, 25(OH)D3, 25(OH)D2, 24,25(OH)2D3, and 24,25(OH)2D2. Chromatographic separation was achieved on a pentaflurophenyl column with 3 mM ammonium formate water/methanol [A] and 3 mM ammonium formate methanol/isopropanol [B] mobile phase components. Detection was by positive ion electrospray tandem mass spectrometry with the EVOQ elite triple quadrupole mass spectrometer with an Advance ultra-high-performance liquid chromatograph and online extraction system. Calibration standards of each metabolite prepared in brain matrices were used to validate the detection range, precision, accuracy, and recovery. Isotopically labelled analogues, 1,25(OH)2D3-d3, 25(OH)D3-c5, and 24,25(OH)2D3-d6, served as the internal standards for the closest molecular-related metabolite in all measurements. Standards between 1 fg/mL and 10 ng/mL were injected with a resulting linear range between 0.001 and 1 ng, with an LLOD and LLOQ of 1 pg/mL and 12.5 pg/mL, respectively. The intra-/inter-day precision and accuracy for measuring brain vit-D metabolites ranged between 0.12-11.53% and 0.28-9.11%, respectively. Recovery in acetonitrile ranged between 99.09 and 106.92% for all metabolites. Collectively, the sensitivity and efficiency of our method supersedes previously reported protocols used to measure vit-D and to our knowledge, the first protocol to reveal the abundance of 25(OH)D2, 1,25(OH)D2, and 24,25(OH)2D2, in brain tissue of any species. This technique may be important in supporting the future advancement of pre-clinical research into the function of vit-D in neurophysiological and neuropsychiatric disorders, and neurodegeneration.

Association between ageing, brain chemistry and white matter volume revealed with complementary MRI and FTIR brain imaging.

Magnetic resonance imaging (MRI) is the gold standard method to study brain anatomy in vivo. Using MRI, subtle alterations to white matter structures in the brain are observed prior to cognitive decline associated with the ageing process, and neurodegenerative diseases such as Alzheimer's disease. Detection of such alterations provides hope for early clinical diagnosis. While MRI is essential to detect subtle alterations to brain structure in vivo, the technique is less suited to study and image the distribution of biochemical markers within specific brain structures. Consequently, the chemical changes that drive, or are associated with MRI-detectable alterations to white matter are not well understood. Herein, we describe (to the best of our knowledge) the first application of a complementary imaging approach that incorporates in vivo MRI with ex vivo Fourier transform infrared (FTIR) spectroscopic imaging on the same brain tissue. The combined workflow is used to detect and associate markers of altered biochemistry (FTIR) with anatomical changes to brain white matter (MRI). We have applied this combination of techniques to the senescence accelerated murine prone strain 8 (SAMP8) mouse model (n = 6 animals in each group, analysed across two ageing time points, 6 and 12 months). The results have demonstrated alterations to lipid composition and markers of disturbed metabolism during ageing are associated with loss of white matter volume.

Short-term consumption of alcohol (vodka) mixed with energy drink (AMED) attenuated alcohol-induced cerebral capillary disturbances and neuroinflammation in adult wild-type mice.

Background: The ingestion of combinatory Alcohol Mixed with Energy Drink (AMED) beverages continues to increase markedly, particularly among young adults. Some studies suggest detrimental health effects related to the combination of alcohol with energy drink formulations; however, the consumption of AMED has not been investigated in context of the cerebral microvasculature or neuroinflammation. We hypothesized that cerebral capillary integrity and glial cells are particularly vulnerable to the combination of AMED.Methods:12-week old wild-type C57BL/6J mice were orally gavaged with either vehicle (water), alcohol (vodka), an energy drink (MotherTM), or a combination AMED, daily for five days. Thereafter, mice were sacrificed, blood alcohol concentrations were analysed and cryosections of brain specimens were subjected to confocal immunofluorescent analysis for measures of cerebral capillary integrity via immunoglobulin G (IgG), and markers of neuroinflammation, ionized-calcium-binding-adaptor-molecule 1 (Iba1) and Glial-Fibrillary-Acidic-Protein (GFAP). Proinflammatory cytokines, IL-2, IL-17A, IFN-ϒ, and anti-inflammatory cytokines, IL-4, IL-6 and IL-10, were also measured in serum.Results: Consistent with previous studies, cerebral capillary dysfunction and astroglial cell activation were markedly greater in the alcohol-only group (AO); however, the AO-induced effects were profoundly attenuated with the AMED combination. Mice maintained on AO and AMED interventions exhibited a moderate increase in microglial recruitment. There were no significant changes in pro-inflammatory nor anti-inflammatory cytokines in ED or AMED treated mice.Conclusion: This study suggests that paradoxically the acute detrimental effects of alcohol on cerebral capillary integrity and astrogliosis are counteracted with the co-provision of an ED, rich in caffeine and taurine and containing B-group vitamins.

Cognitive Deficits in Type-1 Diabetes: Aspects of Glucose, Cerebrovascular and Amyloid Involvement.

The evidence shows that individuals with type-1 diabetes mellitus (T1DM) are at greater risk of accelerated cognitive impairment and dementia. Although, to date the mechanisms are largely unknown. An emerging body of literature indicates that dysfunction of cerebral neurovascular network and plasma dyshomeostasis of soluble amyloid-ß in association with impaired lipid metabolism are central to the onset and progression of cognitive deficits and dementia. However, the latter has not been extensively considered in T1DM. Therefore, in this review, we summarised the literature concerning altered lipid metabolism and cerebrovascular function in T1DM as an implication for potential pathways leading to cognitive decline and dementia.

Chronic high fat feeding paradoxically attenuates cerebral capillary dysfunction and neurovascular inflammation in Senescence-Accelerated-Murine-Prone Strain 8 mice.

Background: A body of epidemiological, clinical and preclinical studies suggest increased risk for cerebro- and cardio-vascular disease associated with dietary ingestion of long-chain saturated fatty acids (LCSFA). In wild-type rodent models, chronic ingestion of LCSFA diets are associated with increased cerebral capillary permeability, heightened neurovascular inflammation and poorer cognitive performance. However, recent studies suggest that diets enriched in fat may paradoxically attenuate elements of the ageing phenotype via a caloric support axis.Objective: The purpose of this study was to explore the effects of dietary LCSFA on cerebral capillary integrity and neurovascular inflammation in an established model of accelerated ageing, Senescence-Accelerated-Murine-Prone Strain 8 (SAMP8) mice.Methods: From 6 weeks of age, SAMP8 mice and age-matched controls were randomised to either normal chow, or to an LCSFA-enriched diet, for either 12 or 34 weeks. An additional group of SAMP8 mice were provided the LCSFA-enriched diet for 12 weeks followed by the provision of ordinary low-fat chow for 22 weeks. Ex vivo measures of cerebrovascular integrity, neurovascular inflammation and astrocytic activation, were determined via 3-dimensional immunofluorescent confocal microscopy methodologies.Results: LCSFA-fed SAMP8 mice had markedly attenuated cerebral capillary dysfunction concomitant with reduced microglial activation. In SAMP8 mice transiently maintained on an LCSFA diet for 12 weeks, suppression of neurovascular inflammation persisted. Marked hippocampal astrogliosis was evident in LCSFA-fed mice when compared to SAMP8 mice maintained on ordinary chow.Conclusion: The findings from this study support the notion that high-fat, potentially ketogenic diets, may confer neuroprotection in SAMP8 mice through a vascular-support axis.

A Systematic Review of the Valproic-Acid-Induced Rodent Model of Autism.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterised by repetitive behaviours, cognitive rigidity/inflexibility, and social-affective impairment. Unfortunately, few pharmacological treatments exist to alleviate these socio-behavioural impairments. Prenatal administration of valproic acid (VPA) has become an accepted animal model of ASD and has been extensively used to explore new pharmacotherapies in rodents. We conducted a systematic review of the behavioural impairments induced by the VPA model in rodents, with specific reference to 3 core socio-behavioural alterations associated with ASD: repetitive behaviours, cognitive rigidity/inflexibility, and social-affective impairment. We systematically reviewed studies attempting to alleviate these core behavioural alterations using pharmacological means. We include 132 studies exploring the prenatal effects of VPA in rodents. Gestational exposure to VPA in rodents has significant effects on rodent-equivalent measures of the 3 core behavioural traits characteristic of ASD in humans, inducing social impairments, repetitive behaviour, and cognitive rigidity/inflexibility after birth. This model's validity has seen it used to test potential drug treatments for ASD and is likely to continue doing so. We conclude the rodent VPA model may be suitable to examine future therapeutic interventions for ASD, providing an overview of the progress made so far.

Genetic, environmental and biomarker considerations delineating the regulatory effects of vitamin D on central nervous system function.

Studies show that vitamin D (vit-D) (25(OH)D), the bioactive metabolite (1,25(OH)2D3) and vit-D receptors (vit-D receptor; protein disulphide isomerase, family A member 3) are expressed throughout the brain, particularly in regions pivotal to learning and memory. This has led to the paradigm that avoiding vit-D deficiency is important to preserve cognitive function. However, presently, it is not clear if the common clinical measure of serum 25(OH)D serves as a robust surrogate marker for central nervous system (CNS) homeostasis or function. Indeed, recent studies report CNS biosynthesis of endogenous 25(OH)D, the CNS expression of the CYP group of enzymes which catalyse conversion to 1,25(OH)2D3 and thereafter, deactivation. Moreover, in the periphery, there is significant ethnic/genetic heterogeneity in vit-D conversion to 1,25(OH)2D3 and there is a paucity of studies which have actually investigated vit-D kinetics across the cerebrovasculature. Compared with peripheral organs, the CNS also has differential expression of receptors that trigger cellular response to 1,25(OH)2D3 metabolites. To holistically consider the putative association of peripheral (blood) abundance of 25(OH)D on cognitive function, herein, we have reviewed population and genetic studies, pre-clinical and clinical intervention studies and moreover have considered potential confounders of vit-D analysis.

Dietary saturated fats and apolipoprotein B48 levels are similarly associated with cognitive decline in healthy older aged Australians.

BACKGROUND AND OBJECTIVES: As the incidence and prevalence of Alzheimer's disease increases, so does the body of epidemiological and clinical research that suggests a relationship between dietary fatty acids, in particular saturates, and cognitive decline. In this study, we investigated the association between serum apolipoprotein B48 (apoB48), saturated fatty acid intake and consumption behaviour, and cognitive performance, in healthy, older aged Australians. METHODS AND STUDY DESIGN: We retrospectively analysed fasted serum apoB48 concentrations, food frequency questionnaire, and cognitive performance data collected from 147 participants (98F|49M) over the age of 50. We used Spearman's correlations and a nested domain model to evaluate the relationship between serum apoB48, dietary behaviour and measures of cognitive performance. RESULTS: Overall, we found that higher fasted apoB48 concentrations, and/or dietary behaviours which led to increased dietary consumption of diets high in saturated fatty acids, were inversely associated with cognition. Interestingly however, dietary behaviour patterns of saturated fatty acid consumption and serum apoB48 were linked with better secondary memory and perceptual speed, respectively. CONCLUSIONS: This is the first time that fasted apoB48 has been implicated as a biomarker for cognitive decline and Alzheimer's disease risk.

Blood-brain barrier disturbances in diabetes-associated dementia: Therapeutic potential for cannabinoids.

Type-2 diabetes (T2D) increases the risk of dementia by ˜5-fold, however the mechanisms by which T2D increases dementia risk remain unclear. Evidence suggests that the heightened inflammation and oxidative stress in T2D may lead to disruption of the blood-brain barrier (BBB), which precedes premature cognitive decline. Studies show that vascular-targeted anti-inflammatory treatments protect the BBB by attenuating neuroinflammation, and in some studies attenuate cognitive decline. Yet, this potential pathway is understudied in T2D-associated cognitive impairment. In recent years, therapeutic potential of cannabinoids has gained much interest. The two major cannabinoids, cannabidiol and tetrahydrocannabinol, exert anti-inflammatory and vascular protective effects, however few studies report their potential for reversing BBB dysfunction, particularly in T2D. Therefore, in this review, we summarize the current findings on the role of BBB dysfunction in T2D-associated dementia and consider the potential therapeutic use of cannabinoids as a protectant of cerebrovascular BBB protection.

The differential effects of fatty acids on enterocytic abundance of amyloid-beta.

BACKGROUND: Consumption of a Western-styled diet enriched in saturated fatty acids (SFA) relative to polyunsaturated fatty acids is positively associated with risk for Alzheimer's disease. Whilst potential causal mechanism are unclear, there is increasing evidence that chronic ingestion of SFA enriched diets promote increase the plasma levels of lipoprotein-associated amyloid-ß (Aß). However, the effects of dietary mono- and poly-unsaturated fats (MUFA/PUFA) on nascent lipoprotein Aß abundance have not been previously reported. METHODS: Wild-type C57BL/6 J mice were maintained on low-fat control chow (LF) or diets enriched in either SFA, MUFA, or PUFA for 9 months. Enterocytic abundance of Aß was determined with quantitative immunofluorescent microscopy and plasma Aß was measured by ELISA. RESULTS: The chronic ingestion of SFA-enriched diet increased the enterocytic abundance and plasma concentration of Aß compared to LF control mice. The mice maintained on MUFA or PUFA diet showed comparable enterocytic and plasma Aß levels to the LF control mice. CONCLUSIONS: The data indicates that a diet enriched in SFA significantly increases the enterocytic Aß production and secretion into the circulation, whilst MUFA and PUFA enriched diet do not exert such effects.

A Multimodal Spectroscopic Imaging Method To Characterize the Metal and Macromolecular Content of Proteinaceous Aggregates ("Amyloid Plaques").

Alzheimer's disease (AD) is a major international health and economic concern. A key pathological feature of AD is so-called "amyloid-ß-plaques", or "Aß-plaques", which are deposits of aggregated protein, enriched with the Aß fragment of amyloid precursor protein. Despite their name, the deposits are not pure Aß and have a heterogeneous, chemically complex composition that can include multiple proteins, lipids, and metal ions (Fe, Cu, or Zn). Despite extensive research, it is still uncertain whether Aß-plaques are a cause or a consequence of AD pathology. Further characterization of the elemental and biochemical composition within and surrounding Aß-plaques, and knowledge of how composition varies with disease state or progression, may provide important insight into the relationship between Aß-plaques and AD pathology. With this aim in mind, herein we demonstrate a multimodal spectroscopic imaging workflow to better characterize the complex composition of Aß-plaques. Our approach incorporates several spectroscopic imaging techniques, such as Fourier transform infrared spectroscopic imaging (FTIR), Raman microscopy, and X-ray fluorescence microscopy (XFM). While FTIR, Raman, and XFM have been used previously, mostly in isolation, to study Aß-plaques, application of all three techniques, in combination with histology and fluorescence microscopy, has not been reported previously. We demonstrate that a multimodal workflow, incorporating all three methods on adjacent or serial tissue sections, can reveal substantial complementary information about the biochemical and elemental composition of Aß-plaques. Information revealed by the method includes the relative content and distribution of aggregated protein, total lipid, lipid esters, cholesterol, and metals (Fe, Cu, or Zn).

Pharmacological modulation of dietary lipid-induced cerebral capillary dysfunction: Considerations for reducing risk for Alzheimer's disease.

An increasing body of evidence suggests that cerebrovascular dysfunction and microvessel disease precede the evolution of hallmark pathological features that characterise Alzheimer's disease (AD), consistent with a causal association for onset or progression. Recent studies, principally in genetically unmanipulated animal models, suggest that chronic ingestion of diets enriched in saturated fats and cholesterol may compromise blood-brain barrier (BBB) integrity resulting in inappropriate blood-to-brain extravasation of plasma proteins, including lipid macromolecules that may be enriched in amyloid-ß (Aß). Brain parenchymal retention of blood proteins and lipoprotein bound Aß is associated with heightened neurovascular inflammation, altered redox homeostasis and nitric oxide (NO) metabolism. Therefore, it is a reasonable proposition that lipid-lowering agents may positively modulate BBB integrity and by extension attenuate risk or progression of AD. In addition to their robust lipid lowering properties, reported beneficial effects of lipid-lowering agents were attributed to their pleiotropic properties via modulation of inflammation, oxidative stress, NO and Aß metabolism. The review is a contemporary consideration of a complex body of literature intended to synthesise focussed consideration of mechanisms central to regulation of BBB function and integrity. Emphasis is given to dietary fat driven significant epidemiological evidence consistent with heightened risk amongst populations consuming greater amounts of saturated fats and cholesterol. In addition, potential neurovascular benefits associated with the use of hypolipidemic statins, probucol and fenofibrate are also presented in the context of lipid-lowering and pleiotropic properties.

Serum 25-hydroxyvitamin D is associated with reduced verbal episodic memory in healthy, middle-aged and older adults.

BACKGROUND: There is increasing evidence supporting an association of higher serum vitamin D concentration with better cognitive performance in older individuals. However, to date, consideration of the putative association between vitamin D and cognition has been based principally on studies investigating clinical participant samples manifesting vitamin D deficiency, particularly in older people. Moreover, relationships between vitamin D and cognition are typically not considered in the context of counter-regulatory calcium-modulating hormones or calcium homeostasis. OBJECTIVE: Serum vitamin D/bioactive (ionised) calcium/parathyroid hormone homeostasis was considered in the context of cognitive performance in healthy, middle-aged and older individuals. DESIGN: A cross-sectional sample of 179 participants between the ages of 47-84 years was recruited for this study (114 females, 65 males). Participants provided fasting blood samples for analysis of serum 25-hydroxyvitamin D levels, ionised calcium (iCa) and parathyroid hormone (PTH) and completed cognitive measures of verbal episodic learning and memory. RESULTS: Serum 25-hydroxyvitamin D concentrations were negatively associated (with and without covariates of age, gender, depression and NART scores, iCa, and PTH) with measures of verbal episodic learning and memory, in particular with trial 5 of the Rey Auditory Verbal Learning Test (RAVLT) and long-delay free recall on the RAVLT. CONCLUSION: Overall, the findings from this study suggest an association between higher vitamin D status and poorer performance on verbal episodic memory in middle-aged and older individuals with normal vitamin D-calcium-PTH homeostasis. Despite requiring replication in other participant samples, this is a potentially important finding as it indicates that it may not be beneficial from a cognitive perspective to provide vitamin D supplements in individuals with already adequate vitamin D status.

Nicotine Attenuates Disruption of Blood-Brain Barrier Induced by Saturated-Fat Feeding in Wild-Type Mice.

INTRODUCTION: Emerging evidence suggests that integrity of blood-brain barrier (BBB) is pivotal to pathology and pathogenesis of vascular-based neurodegenerative disorders. We have recently reported BBB protective effects of nutraceutical agents with anti-inflammatory properties in an established dietary-induced BBB dysfunction model. Studies also reported that nicotine exhibits anti-oxidative/-inflammatory effects and improve cognitive impairment in Alzheimer's disease. However there has been no studies reporting the effect of nicotine on high-fat-induced BBB dysfunction. METHODS: In the present study, we investigated the effect of nicotine on BBB integrity and neuro-inflammation in an established mouse model of BBB disruption induced by a diet enriched in saturated fatty acids (SFA). RESULTS: Wild-type C57BL/6J mice were fed chow enriched in SFA (23% w/w) with/without nicotine for 10 weeks. Compared to mice maintained on SFA-free and low-fat (LF) chow (4% w/w), capillary permeability indicated by the parenchymal extravasation of plasma derived IgG, was significantly greater in the SFA treatment group. Nicotine provided concomitantly with the SFA diet significantly attenuated IgG extravasation, however it remained significantly greater than LF-controls. Markers of neurovascular inflammation glial fibrillary acidic protein, cyclooxygenase-2, and glucose regulated protein 78 remained exaggerated in SFA+nicotine treated mice compared to LF-controls. Nicotine did however modestly, but not significantly, improve plasma total anti-oxidative status in SFA fed mice. CONCLUSION: Nicotine moderately attenuated BBB disruption induced by chronic ingestion of high-SFA diet, but had no significant effect on neuroinflammation per se.

Blood-brain barrier dysfunction developed during normal aging is associated with inflammation and loss of tight junctions but not with leukocyte recruitment.

BACKGROUND: Functional loss of blood-brain barrier (BBB) is suggested to be pivotal to pathogenesis and pathology of vascular-based neurodegenerative disorders such as Alzheimer's disease. We recently reported in wild-type mice maintained on standard diets, progressive deterioration of capillary function with aging concomitant with heightened neuroinflammation. However, the mice used in this study were relatively young (12 months of age) and potential mechanisms for loss of capillary integrity were not investigated per se. The current study therefore extended the previous finding to investigate the effect of aging on BBB integrity in aged mice at 24 months and its potential underlying molecular mechanisms. RESULTS: Immunomicroscopy analyses confirmed significantly increased capillary permeability with heightened neuroinflammation in naturally aged 24-month old mice compared to young control at 3 months of age. Aged mice showed significant attenuation in the expression of BBB tight junction proteins, occludin-1 and to lesser extent ZO-1 compared to young mice. In addition, TNF-α in cerebral endothelial cells of aged mice was significantly elevated compared to controls and this was associated with heightened peripheral inflammation. The expression of ICAM-1 and VCAM-1 remained unelevated, and no sign of leukocyte recruitment was observed in aged mice. CONCLUSION: The BBB breakdown that occurs during ordinary aging is associated with inflammation and disruption of tight junction complex assembly but not through leukocyte trafficking.

Neuropsychological performance is positively associated with plasma albumin in healthy adults.

BACKGROUND: Albumin serves a range of physiological functions that are vital to overall brain and cognitive health. Indeed, associations between cognitive performance and albumin have been demonstrated in individuals with chronic liver or kidney disease and in patients with a high urinary excretion of albumin. However, an association of plasma albumin with cognitive performance has not been reported in otherwise healthy participants with clinically acceptable plasma albumin concentrations. METHOD: This study utilized a wide-ranging neuropsychological test battery to investigate the relationship between cognitive performance and plasma albumin homeostasis in 222 healthy participants (143 females) between the ages of 43 and 84 years (mean 65 years). RESULTS: Albumin both with and without the covariates of age, sex and acute-phase proteins was positively associated with enhanced performance on a range of neuropsychological domains including perceptual speed, Stroop and verbal ability. Albumin manifested generally positive but less robust associations with secondary and primary memory. CONCLUSION: The results indicate that there is a positive association between albumin and cognitive performance in physiologically healthy participants free of chronic renal or liver disease.

Long-term probucol therapy continues to suppress markers of neurovascular inflammation in a dietary induced model of cerebral capillary dysfunction.

BACKGROUND: Probucol has been shown to prevent cerebral capillary disturbances characterized by blood-to-brain extravasation of plasma derived proteins and neurovascular inflammation in mice maintained on western-styled diets for 12 weeks. However the effect of probucol on capillary integrity in aging models with capillary dysfunction is not known. METHODS: Wild-type C57BL6 mice were randomized to a low-fat (LF); saturated-fat (SFA); or SFA + Probucol diet for up to12 months of intervention. RESULTS: Mice fed the LF diet had substantially greater parenchymal abundance of plasma derived IgG and apo B lipoproteins at 12 months, compared to LF mice at 3 months of intervention. Markers of neurovascular inflammation were also greater at 12 months in LF fed mice compared to LF mice at 3 months. The SFA diet exacerbated the aging induced parenchymal abundance of IgG and of apo B lipoproteins and neurovascular inflammation at 12 months. The SFA effects were associated with increased production of intestinal lipoprotein amyloid-ß (Aß). The co-provision of probucol with the SFA completely abolished heightened inflammation at 12 months. Probucol attenuated SFA-induced capillary permeability but had only a modest inhibitory effect on parenchymal retention of apoB lipoproteins. The improvements in markers of inflammation and capillary integrity because of probucol correlated with enterocytic genesis of chylomicron Aß. CONCLUSION: In this long-term feeding study, probucol profoundly suppressed dietary SFA induced disturbances in capillary integrity but had a more modest effect on age-associated changes.

The therapeutic potential of probucol and probucol analogues in neurodegenerative diseases.

Neurodegenerative disorders present complex pathologies characterized by various interconnected factors, including the aggregation of misfolded proteins, oxidative stress, neuroinflammation and compromised blood-brain barrier (BBB) integrity. Addressing such multifaceted pathways necessitates the development of multi-target therapeutic strategies. Emerging research indicates that probucol, a historic lipid-lowering medication, offers substantial potential in the realm of neurodegenerative disease prevention and treatment. Preclinical investigations have unveiled multifaceted cellular effects of probucol, showcasing its remarkable antioxidative and anti-inflammatory properties, its ability to fortify the BBB and its direct influence on neural preservation and adaptability. These diverse effects collectively translate into enhancements in both motor and cognitive functions. This review provides a comprehensive overview of recent findings highlighting the efficacy of probucol and probucol-related compounds in the context of various neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and cognitive impairment associated with diabetes.