Frontiers in Clinical Drug Research - Alzheimer Disorders

The blood brain barrier degenerates in many people as they age. This degeneration can lead to inflammation, amyloid accumulation, neuron loss, tangle accumulation and dementia. Damage to the blood brain barrier may involve oxygen radical production through a visfatin mediated mechanism. Several plant medicines have been traditionally used to decrease the progression of Alzheimer’s disease. Antioxidant mechanisms of action have been described for these medicines that may protect the blood brain barrier. These plant medicines provide alternative treatments for Alzheimer’s disease.

Alzheimer's disease (AD) is the most common form of dementia in aged populations.AD is characterized by a progressive decline in memory and cognitive function, accompanied with behavioral changes such as confusion, irritability and aggression, mood swings, language breakdown and eventually long-term memory loss. The most significantly pathological findings in the brains affected by AD are senile plaques (SP), neurofibrillary tangles (NFT) and neuronal loss or degeneration, particularly in the areas connected to the cerebral cortex and hippocampus.The most prominence among these regions is the basal forebrain cholinergic neurons. Many AD studies and clinical trials focus on inhibiting the formation of extracellular senile plaques and intracellular neurofibrillary tangles to prevent or halt disease progression. For example, the Food and Drug Association (FDA) has approved three acetylcholinesterase inhibitors (AChEIs), donepezil, rivastigmine and galantamine as AD therapy. Elevating the neurotransmitter acetylcholine by AChEIs has been shown to benefit cognitive functions in patients. Excitotoxicity caused by glutamatergic synaptic dysfunction contributes to cognitive AD symptoms. Another FDA-approved AD drug, the N-methyl-D-aspartate (NMDA) receptor antagonist memantine, is thought to alleviate the excitotoxicity. To date, however, none of these treatments have been shown to be safe and effective in clinic. Stem cell therapy is a promising therapeutic strategy, which has been shown to replace the neurodegenerative cholinergic neurons and provide exogenous neurotrophic factors in AD brains. Stem cells have been used as therapy of neurodegenerative diseases to deliver RNAi to the brains and regulate the expression of neprilysin, an amyloid-β (Aβ)-degrading enzyme. More recently, stem cells, especially induced pluripotent stem cells (IPSCs), have been used for AD modeling and drug screening. However, effective drugs or other interventions that stop or delay progression of AD remain elusive. Due to the multifaceted features of AD, further investigations of AD therapies are necessary. This review will discuss the recent progress of stem cell strategies for AD modeling and therapy.

Alzheimer’s disease (AD) is the most common cause of dementia globally. The prevalence has increased dramatically with an aging population. Although considerable progress has been made over the last few decades in understanding the pathophysiology of AD, early and accurate diagnosis of the disorder is still a formidable challenge, and there is currently no effective treatments available to slow down disease progression. The fundamental issue on this disadvantage is largely due to a lack of reliable biomarkers for neurodegeneration in the brain. However, mounting evidence has shown that except the brain, the eye, particularly the retina, is also affected in AD. Because of its transparent nature and ease of accessibility, the eye can serve as a ‘window’ into the brain. Advanced imaging technologies enable observation of changes in the retina in real time, e.g. measurement of thickness of the retinal nerve fibre layer (RNFL) by coherence tomography (OCT), detection of changes in the optic nerve head (ONH) by confocal scanning laser ophthalmoscopy (cSLO), and monitoring of retinal neuronal apoptosis by DARC (Detection of Apoptosing Retinal Cells). In addition to the ocular structural changes in AD patients, similar pathological mechanisms identified in the brain have also been established in the retina, including increased amyloid-ß (Aß) deposition and tau pathology. Furthermore, AD-related changes in the retina have also been observed in eye diseases, including glaucoma and age-related macular degeneration (AMD), and targeting of Aß has been demonstrated to be neuroprotective for those eye diseases. This review focuses on the recent advances in ocular changes, particularly retinal neurodegeneration in AD, discusses pathological similarities between AD and eye diseases, and highlights the potential of retinal imaging in identification of promising biomarkers for early AD.

Alzheimer’s disease (AD) is a neurodegenerative age related disease in which patients of age 65 or more suffer from memory impairment problems. This disease is related to the nervous system degradation and various pathophysiological conditions have been identified such as formation of β-amyloid and plaques, nerve degeneration, neurotransmitter depletion, accumulation of toxins, oxidative stress and inflammation. Local RAS system in the brain is different from vascular RAS and play an important role in pathophysiology of AD. RAS system modulates inflammatory processes, neurotransmitter activity and amyloid and plaque formation. Angiotensin II, a vasoconstriction peptide of RAS system also induces neuronal cell loss by the process of cell senescence. Genetic polymorphism is also an important factor for pathophysiology and treatment of AD. No treatment is available which can eradicate AD completely; only prophylactic treatments are available which gives only prophylactic relief. Treatments are given which improve the pathophysiological condition of the disease and restore the brain cells activity. Treatment approach includes prevention of β amyloid and plaque formation, restoration of neurotransmitter system, prevention of oxidative stress and inflammation. Other than allopathic medicines, traditional system of medicines also have number of herbs and plants which have the property of learning and memory improvement via different mechanism of actions.

Mass spectrometry (MS) has advanced the diagnosis of Alzheimer's disease. In the present chapter, applications of mass spectrometry for the diagnosis of Alzheimer's disease were summarized. Mass spectrometry showed new exciting results, offered high sensitivity (in the femtomolar range), showed high selectivity, has better accuracy, offered high throughput, were extremely rapid (the entire process required few minutes) and can be used for quantitative, qualitative and imaging. Recent mass spectrometry techniques based on nanotechnologies replaced some of the classical MS techniques. These new technologies improved the diagnosis of Alzheimer's disease. Mass spectrometry covered wide range of Alzheimer's disease biomarkers such as amyloid β, total tau protein (t-tau), α-synuclein, posttranslational modification (phosphorylated tau protein, protein S-nitrosation (SNO), racemization, methylation, chlorination and others) and metals ions. From the analytical point of view, mass spectrometry offered detection of large number of biomarkers in a single test. Mass spectrometry has significantly advanced Alzheimer's diagnosis of living patient and postmortal. Monitoring Alzheimer's biomarkers using MS is very promising for the diagnosis in early stages of the disease. However, the proper interpretation of MS profiling is critical and requires careful investigations. Furthermore, the identification of the biomarkers using MS profile is affected by many key variables that have to be considered during the analysis.

Decreasing brain metabolism is a substantive cause of cognitive abnormalities in Alzheimer´s Disease (AD), although this hypo-metabolism is poorly understood, i.e. is not known if it is primary or secondary. Neuron ion homeostasis and thereby synapsis are a crucial and highly energy demanding processes, and one of the hallmarks of AD is the loss of synapsis in defined regions of the brain. Until today, alterations in mitochondrial energy supply have been considered the main concern due to in aging rat neuron model, mitochondria are both chronically depolarized and produce more reactive oxygen species with age. Thereby, impoverished mitochondrial function has been actively studied trying to reverse and recover ATP generation. Today, after more than 100 years that Alois Alzheimer described Augusta D., patients still die in the same way, in spite multiple treatments, multiple theories, multiple studies and unfruitful clinical trials. We believe that the unraveling of the unsuspected intrinsic property of melanin to transform visible and invisible light into chemical energy through the dissociation of the water molecule, as chlorophyll in plants, will mark a before and after, this is: a new frontier, in the understanding and treatment of the nightmare of the XXI century: Alzheimer´s Disease.

Isaria japonica (IJ), is an entomopathogenic fungus that is grown on pupae of the silkworm Bombyx mori for its medicinal properties. Its extracts have potential neuro-protective effects. An extract reversed astrogliosis in the CA3 area of the hippocampus of aged mice. The CA3 area is responsible for spatial pattern association and completion, detection of novel situations, and short-term memory. This finding led us to the development of treatments to improve age-related impairment of patients with Alzheimer’s disease (AD). Acute and subchronic toxicity and chemical profiling of the extract were conducted for the assessments of medical use. We are now evaluating preclinical trials with AD patients. For the diagnosis of AD, magnetic resonance imaging (MRI) enabled the detection of the previously invisible pathological alterations in a mouse sclerosis model with autoimmune encephalomyelitis. Magnetic resonance spectroscopy (MRS) showed that demyelination regions in some multiple screlosis (MS) patients had increased lactic acid content, suggesting the presence of ischemic events. These results show that products derived from IJ may prevent or reduce the impact of dementia, especially AD, and MRI and MRS could lead widely to the diagnosis of neurological diseases.