P3-339: Passage of human intravenous immunoglobulins through the blood-brain barrier in vivo
: Implications for the treatment of Alzheimer's disease

Background: Alzheimer’s disease (AD) is the most common form of dementia in the elderly. It is characterized as a multi-factorial disorder with a prevalent genetic component. Due to the unknown etiology, current treatment based on acetylcholinesterase (AChE) inhibitors and N–methyl-D-aspartate receptors (NMDAR) antagonist is effective only temporary. It seems that curative treatment will necessarily be complex due to the multifactorial nature of the disease. In this context, the so-called “multi-targeting" approach has been established. Objectives: The aim of this study was to develop a multi-target-directed ligand (MTDL) combining the support for the cholinergic system by inhibition of AChE and at the same time ameliorating the burden caused by glutamate excitotoxicity mediated by the NMDAR receptors. Methods: We have applied common approaches of organic chemistry to prepare a hybrid of 6-chlorotacrine and memantine. Then, we investigated its blocking ability towards AChE and NMDRS in vitro, as well as its neuroprotective efficacy in vivo in the model of NMDA-induced lessions. We also studied cytotoxic potential of the compound and predicted the ability to cross the blood-brain barrier. Results: novel molecule formed by combination of 6-chlorotacrine and memantine proved to be a promising multipotent hybrid capable of blocking the action of AChE as well as NMDARs. The presented hybrid surpassed the AChE inhibitory activity of the parent compound 6-Cl-THA twofold. According to results it has been revealed that our novel hybrid blocks NMDARs in the same manner as memantine, potently inhibits AChE and is predicted to cross the blood-brain barrier via passive diffusion. Finally, the MTDL design strategy was indicated by in vivo results which showed that the novel 6-Cl-THA-memantine hybrid displayed a quantitatively better neuroprotective effect than the parent compound memantine. Conclusion: We conclude that the combination of two pharmacophores with a synergistic mechanism of action into a single molecule offers great potential for the treatment of CNS disorders associated with cognitive decline and/or excitotoxicity mediated by NMDARs.

Download Full-text

Do Periodontal Pathogens or Associated Virulence Factors Have a Deleterious Effect on the Blood-Brain Barrier, Contributing to Alzheimer’s Disease?

Journal of Alzheimer s Disease ◽

10.3233/jad-215103 ◽

2021 ◽

pp. 1-17

Author(s):

Mhd Ammar Kouki ◽

Anna Barlach Pritchard ◽

Jane Elizabeth Alder ◽

StJohn Crean

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Blood Brain Barrier ◽

Virulence Factors ◽

Current Knowledge ◽

Brain Barrier ◽

Periodontal Pathogens ◽

Blood Brain

The central nervous system (CNS) is protected by a highly selective barrier, the blood-brain barrier (BBB), that regulates the exchange and homeostasis of bloodborne molecules, excluding xenobiotics. This barrier forms the first line of defense by prohibiting pathogens from crossing to the CNS. Aging and chronic exposure of the BBB to pathogens renders it permeable, and this may give rise to pathology in the CNS such as Alzheimer’s disease (AD). Researchers have linked pathogens associated with periodontitis to neuroinflammation and AD-like pathology in vivo and in vitro. Although the presence of periodontitis-associated bacteria has been linked to AD in several clinical studies as DNA and virulence factors were confirmed in brain samples of human AD subjects, the mechanism by which the bacteria traverse to the brain and potentially influences neuropathology is unknown. In this review, we present current knowledge about the association between periodontitis and AD, the mechanism whereby periodontal pathogens might provoke neuroinflammation and how periodontal pathogens could affect the BBB. We suggest future studies, with emphasis on the use of human in vitro models of cells associated with the BBB to unravel the pathway of entry for these bacteria to the CNS and to reveal the molecular and cellular pathways involved in initiating the AD-like pathology. In conclusion, evidence demonstrate that bacteria associated with periodontitis and their virulence factors are capable of inflecting damage to the BBB and have a role in giving rise to pathology similar to that found in AD.

Download Full-text

β-Amyloid Protein Induces Mitophagy-Dependent Ferroptosis Through the CD36/PINK/PARKIN Pathway Leading to Blood-Brain Barrier Destruction in Alzheimer's Disease

10.21203/rs.3.rs-1087555/v1 ◽

2021 ◽

Author(s):

li Jianhua ◽

Li mengyu ◽

Ge Yangyang ◽

Chen Jiayi ◽

Ma Jiamin ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanism ◽

Blood Brain Barrier ◽

Amyloid Β ◽

Brain Barrier ◽

Blood Brain ◽

Bbb Permeability

Abstract Background Blood-brain barrier (BBB) dysfunction may occur in the onset of Alzheimer's disease (AD). While pericytes are a vital part of the neurovascular unit and the BBB, acting as the gatekeeper of the BBB. Amyloid β (Aβ) deposition and neurofibrillary tangles in the brain are the central pathological features of AD. CD36 promotes vascular amyloid deposition and leads to vascular brain damage, neurovascular dysfunction, and cognitive deficits. However, the molecular mechanism in destroying pericytes of the BBB are still unclear. Objectives To investigate the effect of low-dose Aβ1-40 administration on pericyte outcome and BBB injury molecular mechanism. Methods We selected 6-month-old and 9-month-old APP/PS1 mice and wild-type (WT) mice of the same strain, age, and sex as controls. We assessed the BBB by PET/CT. Brain pericytes were extracted and cocultured with endothelial cells (bEnd.3) to generate an in vitro BBB model to observe the effect of Aβ1-40 on the BBB. Furthermore, we explored the intracellular degradation and related molecular mechanisms of Aβ1-40 after being engulfed in cells through CD36. Results BBB permeability and the number of pericytes decreased in APP/PS1 mice. Aβ1-40 increases the permeability of the BBB in an in vivo model and downregulates the expression of CD36, which reversed the Aβ-induced changes in BBB permeability. Aβ1-40 was phagocytized in pericytes with high expression of CD36. We observed that this molecule inhibited pericyte proliferation, caused mitochondrial damage, and increased mitophagy. Finally, we confirmed that Aβ1-40 induced pericyte mitophagy-dependent ferroptosis through the CD36/PINK1/Parkin pathway. Conclusions PDGFRβ (a marker of pericytes), CD36, and amyloid β colocalized in vitro and in vivo and that Aβ1-40 caused BBB destruction by upregulating the expression of CD36 in pericytes. The mechanism by which Aβ1-40 destroys the BBB involves induction of pericyte mitophagy-dependent ferroptosis through the CD36/PINK1/Parkin pathway.

Download Full-text

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

RSC Advances ◽

10.1039/d0ra06855a ◽

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.

Download Full-text

Probable Causes of Alzheimer’s Disease

Sci ◽

10.3390/sci3010016 ◽

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.

Download Full-text

Exploring the changes of brain immune microenvironment in Alzheimer’s disease based on PANDA algorithm combined with blood brain barrier injury-related genes

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2021.04.014 ◽

2021 ◽

Vol 557 ◽

pp. 159-165

Author(s):

Shiting Lu ◽

Wei Kong ◽

Shuaiqun Wang

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Immune Microenvironment ◽

Blood Brain

Download Full-text

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

Current Pharmaceutical Design ◽

10.2174/1381612827666210927163258 ◽

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.

Download Full-text

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

International Journal of Molecular Sciences ◽

10.3390/ijms19103224 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3224 ◽

Cited By ~ 8

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.

Download Full-text