scholarly journals Blood‐brain barrier insulin resistance decreases insulin uptake and increases amyloid beta uptake in Alzheimer's disease brain

2020 ◽  
Vol 16 (S3) ◽  
Author(s):  
Andrew L Zhou ◽  
Suresh K Swaminathan ◽  
Chaitanya C Gali ◽  
Tyler J Bruinsma ◽  
Geoffry L Curran ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Insulin Resistance ◽  
Alzheimer's Disease ◽  
Blood Brain Barrier ◽  
Amyloid Beta ◽  
Brain Barrier ◽  
Blood Brain ◽  
Insulin Uptake

Distinct uptake kinetics of Alzheimer's disease amyloid beta 40 and 42 at the blood-brain barrier endothelium

2020 ◽  
pp. JPET-AR-2020-000086
Author(s):  
Nidhi Sharda ◽  
Kristen M Ahlschwede ◽  
Geoffry L Curran ◽  
Val J Lowe ◽  
Karunya K. Kandimalla
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Brain Barrier ◽  
Amyloid Beta ◽  
Uptake Kinetics ◽  
Brain Barrier ◽  
Blood Brain ◽  
Kinetics Of

scholarly journals Cerebrovascular insulin receptors are defective in Alzheimerˈs disease

2021 ◽  
Author(s):  
M. Leclerc ◽  
P. Bourassa ◽  
C. Tremblay ◽  
V. Caron ◽  
C. Sugère ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Insulin Resistance ◽  
Alzheimer's Disease ◽  
Blood Brain Barrier ◽  
Insulin Receptors ◽  
Brain Barrier ◽  
List Type ◽  
Blood Brain ◽  
Brain Insulin ◽  
Brain Insulin Resistance

AbstractCentral response to insulin is suspected to be defective in Alzheimer’s disease (AD), but its localization in the brain remains unknown. While most insulin is secreted in the bloodstream by the pancreas, how it interacts with the blood-brain barrier (BBB) to alter brain function remains poorly defined.Here, we show that human and murine cerebral insulin receptors (INSR), particularly the long isoform INSRα-B, are concentrated in microvessels rather than in the parenchyma. Vascular concentrations of INSRα-B were lower in the parietal cortex of subjects diagnosed with AD, positively correlating with cognitive scores, leading to a shift toward a higher INSRα-A/B ratio, consistent with cerebrovascular insulin resistance in the AD brain. Vascular INSRα was inversely correlated with β-amyloid (Aβ) plaques and β-site APP cleaving enzyme 1 (BACE1), but positively correlated with insulin-degrading enzyme (IDE), neprilysin and ABCB1. Using brain cerebral intracarotid perfusion, we found that the transport rate of insulin across the BBB remained very low (<0.03 µl.g-1.s-1) and was not inhibited by an INSR antagonist. However, intracarotid perfusion of insulin induced the phosphorylation of INSRβ which was restricted to microvessels. Such an activation of vascular INSR was blunted in 3xTg-AD mice, suggesting that AD neuropathology induces insulin resistance at the level of the BBB.Overall, the present data in postmortem AD brains and an animal model of AD indicate that defects in the INSR localized at the BBB strongly contribute to brain insulin resistance in AD, in association with Aβ pathology.HighlightsCirculating insulin activates brain insulin receptors in microvessels.BBB INSR contribute to cerebral insulin resistance in AD.Cognitive impairment in AD is associated with a loss of cerebrovascular INSRα-B.Loss of isoform INSRα-B is associated with increased BACE1 activity.SummaryLeclerc et al. show that circulating insulin activates cerebral insulin receptor localized on the blood-brain-barrier level (BBB), not in the parenchyma. Experiments with human brain samples and animal models provide evidence that INSR at the BBB are impaired in Alzheimer’s disease, thereby contributing to brain insulin resistance.

scholarly journals A first-principles study on potential chelation agents and indicators of Alzheimer's disease

RSC Advances ◽  
2020 ◽  
Vol 10 (58) ◽  
pp. 35574-35581
Author(s):  
Bryan Wang ◽  
Xuan Luo
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Serum ◽  
Blood Brain Barrier ◽  
First Principles ◽  
Brain Barrier ◽  
Serum Transferrin ◽  
Human Serum Transferrin ◽  
First Principles Study ◽  
Blood Brain

Human-serum transferrin is involved in the transportation of aluminum across the blood–brain barrier.

scholarly journals Probable Causes of Alzheimer’s Disease

Sci ◽  
2021 ◽  
Vol 3 (1) ◽  
pp. 16
Author(s):  
James David Adams
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Lactic Acid ◽  
Blood Brain Barrier ◽  
Transient Receptor Potential ◽  
Brain Barrier ◽  
Folate Intake ◽  
Blood Brain ◽  
Age Related ◽  
The Brain

A three-part mechanism is proposed for the induction of Alzheimer’s disease: (1) decreased blood lactic acid; (2) increased blood ceramide and adipokines; (3) decreased blood folic acid. The age-related nature of these mechanisms comes from age-associated decreased muscle mass, increased visceral fat and changes in diet. This mechanism also explains why many people do not develop Alzheimer’s disease. Simple changes in lifestyle and diet can prevent Alzheimer’s disease. Alzheimer’s disease is caused by a cascade of events that culminates in damage to the blood–brain barrier and damage to neurons. The blood–brain barrier keeps toxic molecules out of the brain and retains essential molecules in the brain. Lactic acid is a nutrient to the brain and is produced by exercise. Damage to endothelial cells and pericytes by inadequate lactic acid leads to blood–brain barrier damage and brain damage. Inadequate folate intake and oxidative stress induced by activation of transient receptor potential cation channels and endothelial nitric oxide synthase damage the blood–brain barrier. NAD depletion due to inadequate intake of nicotinamide and alterations in the kynurenine pathway damages neurons. Changes in microRNA levels may be the terminal events that cause neuronal death leading to Alzheimer’s disease. A new mechanism of Alzheimer’s disease induction is presented involving lactic acid, ceramide, IL-1β, tumor necrosis factor α, folate, nicotinamide, kynurenine metabolites and microRNA.

Recent Advances in Targeted Drug Delivery Approaches using Lipidic and Polymeric Nanocarriers for the management of Alzheimer’s Disease

2021 ◽  
Vol 27 ◽  
Author(s):  
Dhara Lakdawala ◽  
Md Abdur Rashid ◽  
Farhan Jalees Ahmad
Keyword(s):  
Alzheimer’S Disease ◽  
Drug Delivery ◽  
Alzheimer's Disease ◽  
Blood Brain Barrier ◽  
Targeted Drug Delivery ◽  
Brain Barrier ◽  
Polymeric Nanocarriers ◽  
Blood Brain ◽  
Targeted Drug ◽  
The Brain

: Drug delivery to the brain has remained a significant challenge in treating neurodegenerative disorders such as Alzheimer's disease due to the presence of the blood-brain barrier, which primarily obstructs the access of drugs and biomolecules into the brain. Several methods to overcome the blood-brain barrier have been employed, such as chemical disruption, surgical intervention, focused ultrasound, intranasal delivery and using nanocarriers. Nanocarrier systems remain the method of choice and have shown promising results over the past decade to achieve better drug targeting. Polymeric nanocarriers and lipidic nanoparticles act as a carrier system providing better encapsulation of drugs, site-specific delivery, increased bioavailability and sustained release of drugs. The surface modifications and functionalization of these nanocarrier systems have greatly facilitated targeted drug delivery. The safety and efficacy of these nanocarrier systems have been ascertained by several in vitro and in vivo models. In the present review, we have elaborated on recent developments of nanoparticles as a drug delivery system for Alzheimer's disease, explicitly focusing on polymeric and lipidic nanoparticles.

scholarly journals Dendrimeric Poly(Epsilon-Lysine) Delivery Systems for the Enhanced Permeability of Flurbiprofen across the Blood-Brain Barrier in Alzheimer’s Disease

2018 ◽  
Vol 19 (10) ◽  
pp. 3224 ◽  
Author(s):  
Shafq Al-azzawi ◽  
Dhafir Masheta ◽  
Anna Guildford ◽  
Gary Phillips ◽  
Matteo Santin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Brain Barrier ◽  
Solid Phase ◽  
Synthesis Method ◽  
Delivery Systems ◽  
Brain Barrier ◽  
Target Cells ◽  
Target Tissue ◽  
Blood Brain

Alzheimer’s disease (AD) is a progressive brain disorder and age-related disease characterised by abnormal accumulation of β-amyloid (Aβ). The development of drugs to combat AD is hampered by the lack of therapeutically-active molecules able to cross the blood-brain barrier (BBB). It is agreed that specifically-designed carriers, such as dendrimers, could support the drug penetration across the BBB. The aim of this study was to design biocompatible and biodegradable dendrimeric delivery systems able to carry Flurbiprofen (FP), as drug for AD treatment, across the BBB and liberate it at the target tissue. These dendrons were synthesised using solid-phase peptide synthesis method and characterised by mass spectrometry and fourier-transform infrared spectroscopy (FTIR). The results revealed successful synthesis of dendrons having FP been integrated during the synthesis at their branching ends. Cytotoxicity assays demonstrated the biocompatibility of the delivery systems, whereas HPLC analysis showed high percentages of permeability across an in vitro BBB model for FP-integrated dendrons. Results also revealed the efficiency of drug conjugates on the γ-secretase enzyme in target cells with evidence of eventual drug release by hydrolysis of the carrier. This study demonstrates that the coupling of FP to dendrimeric delivery systems can successfully be achieved during the synthesis of the poly(epsilon-lysine) macromolecules to improve the transport of the active drug across the BBB.

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