Targeting the Progression of Parkinson’s Disease

By the time a patient first presents with symptoms of Parkinson’s disease at the clinic, a significant proportion (50-70%) of the cells in the substantia nigra (SN) has already been destroyed. This degeneration progresses until, within a few years, most of the cells have died. Except for rare cases of familial PD, the initial trigger for cell loss is unknown. However, we do have some clues as to why the damage, once initiated, progresses unabated. It would represent a major advance in therapy to arrest cell loss at the stage when the patient first presents at the clinic. Current therapies for Parkinson’s disease focus on relieving the motor symptoms of the disease, these unfortunately lose their effectiveness as the neurodegeneration and symptoms progress. Many experimental approaches are currently being investigated attempting to alter the progression of the disease. These range from replacement of the lost neurons to neuroprotective therapies; each of these will be briefly discussed in this review. The main thrust of this review is to explore the interactions between dopamine, alpha synuclein and redox-active metals. There is abundant evidence suggesting that destruction of SN cells occurs as a result of a self-propagating series of reactions involving dopamine, alpha synuclein and redox-active metals. A potent reducing agent, the neurotransmitter dopamine has a central role in this scheme, acting through redox metallo-chemistry to catalyze the formation of toxic oligomers of alpha-synuclein and neurotoxic metabolites including 6-hydroxydopamine. It has been hypothesized that these feed the cycle of neurodegeneration by generating further oxidative stress. The goal of dissecting and understanding the observed pathological changes is to identify therapeutic targets to mitigate the progression of this debilitating disease.Key Words: Parkinson’s disease, pathology, redox chemistry, metallo- chemistry, review, iron.     

Pathogenic Mechanisms of Heavy Metal Induced-Alzheimer’s Disease

Alzheimer’s disease is an increasing neurodegenerative disease in the aging population. The disease is associated with toxic chemicals of industrial origin. Industrial processes can result in airborne contamination such as fine dust, and water and soil contamination. In the processes, heavy metals are one of the major environmental pollutants. Also, heavy metals are widely used for many appliances. In particular, heavy metals are seriously toxic to the neural system. In several studies, researchers have emphasized the toxicity of heavy metals such as lead, mercury, and cadmium, as a cause of neurofibrillary tangles, aggregation amyloid beta peptides (AβPs) as well as neuronal cell loss. Based on neurotoxic studies showing that heavy metals induce Alzheimer’s disease, this paper discusses molecular mechanisms by which exposure to heavy metals contributes to the pathogenesis of Alzheimer’s disease. Also, we indicate pathway for heavy metal related Alzheimer’s through integrated analysis based on molecular networks. We suggest that the study of signaling networks contributes to our ability to select significant factors for curing heavy metal induced Alzheimer’s disease.     

Imaging Microglial Activation During Neuroinflammation and Alzheimer’s Disease

Microglial activation is an important pathogenic component of neurodegenerative disease processes. This state of increased inflammation is associated not only with neurotoxic consequences but also neuroprotective effects, e.g., phagocytosis and clearance of amyloid in Alzheimer’s disease. In addition, activation of microglia appears to be one of the major mechanisms of amyloid clearance following active or passive immunotherapy. Imaging techniques may provide a minimally invasive tool to elucidate the complexities and dynamics of microglial function and dysfunction in aging and neurodegenerative diseases. Imaging microglia in vivo in live subjects by confocal or two/multiphoton microscopy offers the advantage of studying these cells over time in their native environment. Imaging microglia in human subjects by positron emission tomography scanning with translocator protein-18 kDa ligands can offer a measure of the inflammatory process and a means of detecting progression of disease and efficacy of therapeutics over time.     

Immune and Inflammatory Determinants Underlying Alzheimer’s Disease Pathology

Journal of Neuroimmune Pharmacology - This study examines the link between peripheral immune changes in perpetuation of the Alzheimer’s disease (AD) neuropathology and cognitive deficits. Our...     

Extracellular Vesicle Biology in Alzheimer’s Disease and Related Tauopathy

Extracellular vesicles (EVs) are physiological vesicles secreted from most eukaryotes and contain cargos of their cell of origin. EVs, and particularly a subset of EV known as exosomes, are emerging as key mediators of cell to cell communication and waste management for cells both during normal organismal function and in disease. In this review, we investigate the rapidly growing field of exosome biology, their biogenesis, cargo loading, and uptake by other cells. We particularly consider the role of exosomes in Alzheimer’s disease, both as a pathogenic agent and as a disease biomarker. We also explore the emerging role of exosomes in chronic traumatic encephalopathy. Finally, we highlight open questions in these fields and the possible use of exosomes as therapeutic targets and agents.     

Implication of Complement System and its Regulators in Alzheimer’s Disease

Alzheimer’s disease (AD) is an age-related neurodegenerative disease that affects approximately 24 million people worldwide. A number of different risk factors have been implicated in AD, however, neuritic (amyloid) plaques are considered as one of the defining risk factors and pathological hallmarks of the disease. Complement proteins are integral components of amyloid plaques and cerebral vascular amyloid in Alzheimer brains. They can be found at the earliest stages of amyloid deposition and their activation coincides with the clinical expression of Alzheimer''s dementia. This review emphasizes on the dual key roles of complement system and complement regulators (CRegs) in disease pathology and progression. The particular focus of this review is on currently evolving strategies for design of complement inhibitors that might aid therapy by restoring the fine balance between activated components of complement system, thus improving the cognitive performance of patients. This review discusses these issues with a view to inspiring the development of new agents that could be useful for the treatment of AD.Key Words: Alzheimer’s disease, neurodegeneration, inflammation, β-amyloid peptide, complement, complement regulators, CD59, complement therapeutics.     

Angiopep-Conjugated Nanoparticles for Targeted Long-Term Gene Therapy of Parkinson’s Disease

Purpose

To prepare an angiopep-conjugated dendrigraft poly-L-lysine (DGL)-based gene delivery system and evaluate the neuroprotective effects in the rotenone-induced chronic model of Parkinson’s disease (PD).

Methods

Angiopep was applied as a ligand specifically binding to low-density lipoprotein receptor-related protein (LRP) which is overexpressed on blood-brain barrier (BBB), and conjugated to biodegradable DGL via hydrophilic polyethyleneglycol (PEG), yielding DGL-PEG-angiopep (DPA). In vitro characterization was carried out. The neuroprotective effects were evaluated in a chronic parkinsonian model induced by rotenone using a regimen of multiple dosing intravenous administrations.

Results

The successful synthesis of DPA was demonstrated via ¹H-NMR. After encapsulating the therapeutic gene encoding human glial cell line-derived neurotrophic factor (hGDNF), DPA/hGDNF NPs showed a sphere-like shape with the size of 119?±?12 nm and zeta potential of 8.2?±?0.7 mV. Angiopep-conjugated NPs exhibited higher cellular uptake and gene expression in brain cells compared to unmodified counterpart. The pharmacodynamic results showed that rats in the group with five injections of DPA/hGDNF NPs obtained best improved locomotor activity and apparent recovery of dopaminergic neurons compared to those in other groups.

Conclusion

This work provides a practical non-viral gene vector for long-term gene therapy of chronic neurodegenerative disorders.     

Neural and Immune Mechanisms in the Pathogenesis of Parkinson’s Disease

Although almost 50 years have passed since impaired dopaminergic transmission was identified as the main neurochemical defect in Parkinson’s disease (PD), the cause of the disease remains unknown. A restricted number of biological mechanisms are likely to contribute to the process of cell death in the nigrostriatal pathway. These mechanisms include mitochondrial defects and enhanced formation of reactive oxygen species—leading to oxidative damage—and abnormal protein aggregation. In addition to or, possibly, intermingled with these mechanisms of neuronal damage there is another crucial factor: neuroinflammation. The inflammatory response associated with cell loss in the dopaminergic nigrostriatal tract and, more in general, the role of immune mechanisms are increasingly recognized in PD pathogenesis. Neuroinflammatory changes have been repeatedly demonstrated, in both neurotoxic and transgenic animal models of PD, as well as in PD patients. Transgenic models based on α-synuclein overexpression, in particular, have provided crucial insights into the correlation between this protein and the dichotomous response that microglia can activate, with the polarization toward a cytotoxic (M1) or cytoprotective (M2) phenotype. Full understanding of such mechanisms may set the ground for a fine tuning of the neuroinflammatory process that accompanies and sustains neurodegeneration, thereby opening new therapeutic perspectives for PD.     

Bayesian Quantitative Disease–Drug–Trial Models for Parkinson’s Disease to Guide Early Drug Development

The problem we have faced in drug development is in its efficiency. Almost a half of registration trials are reported to fail mainly because pharmaceutical companies employ one-size-fits-all development strategies. Our own experience at the regulatory agency suggests that failure to utilize prior experience or knowledge from previous trials also accounts for trial failure. Prior knowledge refers to both drug-specific and nonspecific information such as placebo effect and the disease course. The information generated across drug development can be systematically compiled to guide future drug development. Quantitative disease-drug-trial models are mathematical representations of the time course of biomarker and clinical outcomes, placebo effects, a drug's pharmacologic effects, and trial execution characteristics for both the desired and undesired responses. Applying disease-drug-trial model paradigms to design a future trial has been proposed to overcome current problems in drug development. Parkinson's disease is a progressive neurodegenerative disorder characterized by bradykinesia, rigidity, tremor, and postural instability. A symptomatic effect of drug treatments as well as natural rate of disease progression determines the rate of disease deterioration. Currently, there is no approved drug which claims disease modification. Regulatory agency has been asked to comment on the trial design and statistical analysis methodology. In this work, we aim to show how disease-drug-trial model paradigm can help in drug development and how prior knowledge from previous studies can be incorporated into a current trial using Parkinson's disease model as an example. We took full Bayesian methodology which can allow one to translate prior information into probability distribution.     

NMDA Neurotransmission Dysfunction in Behavioral and Psychological Symptoms of Alzheimer’s Disease

Dementia has become an all-important disease because the population is aging rapidly and the cost of health care associated with dementia is ever increasing. In addition to cognitive function impairment, associated behavioral and psychological symptoms of dementia (BPSD) worsen patient’s quality of life and increase caregiver’s burden. Alzheimer’s disease is the most common type of dementia and both behavioral disturbance and cognitive impairment of Alzheimer’s disease are thought to be associated with the N-methyl-D-aspartate (NMDA) dysfunction as increasing evidence of dysfunctional glutamatergic neurotransmission had been reported in behavioral changes and cognitive decline in Alzheimer’s disease. We review the literature regarding dementia (especially Alzheimer’s disease), BPSD and relevant findings on glutamatergic and NMDA neurotransmission, including the effects of memantine, a NMDA receptor antagonist, and NMDA-enhancing agents, such as D-serine and D-cycloserine. Literatures suggest that behavioral disturbance and cognitive impairment of Alzheimer’s disease may be associated with excitatory neurotoxic effects which result in impairment of neuronal plasticity and degenerative processes. Memantine shows benefits in improving cognition, function, agitation/aggression and delusion in Alzheimer’s disease. On the other hand, some NMDA modulators which enhance NMDA function through the co-agonist binding site can also improve cognitive function and psychotic symptoms. We propose that modulating NMDA neurotransmission is effective in treating behavioral and psychological symptoms of Alzheimer’s disease. Prospective study using NMDA enhancers in patients with Alzheimer’s disease and associated behavioral disturbance is needed to verify this hypothesis.     

Anti-Oxidants in Parkinson’s Disease Therapy: A Critical Point of View

Parkinson’s disease (PD) is a degenerative neurological syndrome, which is characterized by the preferential death of dopaminergic (DAergic) neurons in the Substantia Nigra. The pathogenesis of this disorder remains poorly understood and PD is still incurable. Current drug treatments are aimed primarily for the treatment of symptoms to improve the quality of life. Therefore, there is a need to find out new therapeutic strategies that not only provide symptomatic relief but also halt or reverse the neuronal damage hampering PD progression. Oxidative stress has been identified as one of the major contributors for the nigral loss in both sporadic and genetic forms of PD. In this review we first evaluate the current literature that links oxidative stress and mitochondrial dysfunction to PD. We then consider the results obtained through the treatment of animal models or PD patients with molecules that prevent oxidative stress or reduce mitochondrial dysfunction.     

Disease-Induced Alterations in Brain Drug Transporters in Animal Models of Alzheimer’s Disease

Purpose

Alzheimer’s disease (AD) may disturb functions of the blood-brain barrier and change the disposition of drugs to the brain. This study assessed the disease-induced changes in drug transporters in the brain capillaries of transgenic AD mice.

Methods

Eighteen drug transporters and four tight junction-associated proteins were analyzed by RT-qPCR in cortex, hippocampus and cerebellum tissue samples of 12–16-month-old APdE9, Tg2576 and APP/PS1 transgenic mice and their healthy age-matched controls. In addition, microvessel fractions enriched from 1-3-month-old APdE9 mice were analyzed using RT-qPCR and Western blotting. Brain transport of methotrexate in APdE9 mice was assessed by in vivo microdialysis.

Results

The expression profiles of studied genes were similar in brain tissues of AD and control mice. Instead, in the microvessel fraction in APdE9 mice, >2-fold alterations were detected in the expressions of 11 genes but none at the protein level. In control mice strains, >5-fold changes between different brain regions were identified for Slc15a2, Slc22a3 and occludin. Methotrexate distribution into hippocampus of APdE9 mice was faster than in controls.

Conclusions

The expression profile of mice carrying presenilin and amyloid precursor protein mutations is comparable to controls, but clear regional differences exist in the expression of drug transporters in brain.

     

Use of Benzodiazepines in Alzheimer’s Disease: A Systematic Review of Literature

Background:

Benzodiazepines are frequently prescribed in patients with Alzheimer’s disease. Unfortunately, studies evaluating their benefits and risks in these patients are limited.

Methods:

Clinical trials focusing on the effect of benzodiazepines on cognitive functions, disease progression, behavioral symptoms, sleep disturbances, and the general frequency of benzodiazepine use were included in this review. Published articles from January 1983 to January 2015 were identified using specific search terms in MEDLINE and PubMed Library according to the recommendations of The Strengthening the Reporting of Observational Studies in Epidemiology initiative.

Results:

Of the 657 articles found, 18 articles met predefined selection criteria and were included in this review (8 on frequency, 5 on cognitive functions, 5 on behavioral and sleep disturbances). The frequency of benzodiazepine use ranged from 8.5% to 20%. Five studies reported accelerated cognitive deterioration in association with benzodiazepine use. Two studies reported clinical efficacy for lorazepam and alprazolam to reduce agitation in Alzheimer’s disease patients. No evidence was found for an improvement of sleep quality using benzodiazepines.

Conclusion:

This systematic review shows a relatively high prevalence of benzodiazepine use but limited evidence for clinical efficacy in Alzheimer’s disease patients. However, there is a paucity of methodologically high quality controlled clinical trials. Our results underscore a need for randomized controlled trials in this area.     

Natural AChE Inhibitors from Plants and their Contribution to Alzheimer’s Disease Therapy

As acetylcholinesterase (AChE) inhibitors are an important therapeutic strategy in Alzheimer’s disease, efforts are being made in search of new molecules with anti-AChE activity. The fact that naturally-occurring compounds from plants are considered to be a potential source of new inhibitors has led to the discovery of an important number of secondary metabolites and plant extracts with the ability of inhibiting the enzyme AChE, which, according to the cholinergic hypothesis, increases the levels of the neurotransmitter acetylcholine in the brain, thus improving cholinergic functions in patients with Alzheimer’s disease and alleviating the symptoms of this neurological disorder. This review summarizes a total of 128 studies which correspond to the most relevant research work published during 2006-2012 (1st semester) on plant-derived compounds, plant extracts and essential oils found to elicit AChE inhibition.