Calcium channel blockers and Alzheimer’s disease

Alzheimer’s disease is characterized by two pathological hallmarks: amyloid plaques and neurofi-brillary tangles. In addition, calcium homeostasis is disrupted in the course of human aging. Recent research shows that dense plaques can cause functional alteration of calcium signals in mice with Alzheimer’s disease. Calcium channel blockers are effective therapeutics for treating Alzheimer’s disease. This review provides an overview of the current research of calcium channel blockers in-volved in Alzheimer’s disease therapy.     

Effects of triptolide on hippocampal microglial cells and astrocytes in the APP/PS1 double transgenic mouse model of Alzheimer’s disease

The principal pathology of Alzheimer's disease includes neuronal extracellular deposition of amyloid-beta peptides and formation of senile pl aques,which in turn induce neuroinflammation in the brain.Triptolide,a natural extract from the vine-like herb Tripterygium wilfordii Hook F,has potent anti-inflammatory and immunosuppressive efficacy.Therefore,we determined if triptolide can inhibit activation and proliferation of microglial cells and astrocytes in the APP/PS1 double transgenic mouse model of Alzheimer's disease.We used 1 or 5 μg/kg/d triptolide to treat APP/PS1 double transgenic mice(aged 4–4.5 months) for 45 days.Unbiased stereology analysis found that triptolide dose-dependently reduced the total number of microglial cells,and transformed microglial cells into the resting state.Further,triptolide(5 μg/kg/d) also reduced the total number of hippocampal astrocytes.Our in vivo test results indicate that triptolide suppresses activation and proliferation of microglial cells and astrocytes in the hippocampus of APP/PS1 double transgenic mice with Alzheimer's disease.     

Metabolomics: a novel approach to identify potential diagnostic biomarkers and pathogenesis in Alzheimer’s disease

Although the pathogenesis of Alzheimer’s disease (AD) is still not fully understood, it is acknowledged that intervention should be made at the early stage. Therefore, identifying biomarkers for the clinical diagnosis is critical. Metabolomics, a novel "omics", uses methods based on low-molecular-weight molecules, with high-throughput evaluation of a large number of metabolites that may lead to the identification of new disease-specific biomarkers and the elucidation of pathophysiological mechanisms. This review discusses metabolomics investigations of AD and potential future developments in this field.     

Degenerative alterations in noradrenergic neurons of the locus coeruleus in Alzheimer’s disease

Mice carrying mutant amyloid-β precursor protein and presenilin-1 genes (APP/PS1 double transgenic mice) have frequently been used in studies of Alzheimer’s disease; however, such studies have focused mainly on hippocampal and cortical changes. The severity of Alzheimer’s disease is known to correlate with the amount of amyloid-β protein deposition and the number of dead neurons in the locus coeruleus. In the present study, we assigned APP/PS1 double transgenic mice to two groups according to age: young mice (5-6 months old) and aged mice (16-17 months old). Age-matched wild-type mice were used as controls. Immunohistochemistry for tyrosine hydroxylase (a marker of catecholaminergic neurons in the locus coeruleus) revealed that APP/PS1 mice had 23% fewer cells in the locus coeruleus compared with aged wild-type mice. APP/PS1 mice also had increased numbers of cell bodies of neurons positive for tyrosine hydroxylase, but fewer tyrosine hydroxylase-positive fibers, which were also short, thick and broken. Quantitative analysis using unbiased stereology showed a significant age-related increase in the mean volume of tyrosine hydroxylase-positive neurons in aged APP/PS1 mice compared with young APP/PS1 mice. Moreover, the mean volume of tyrosine hydroxylase-positive neurons was positively correlated with the total volume of the locus coeruleus. These findings indicate that noradrenergic neurons and fibers in the locus coeruleus are predisposed to degenerative alterations in APP/PS1 double transgenic mice.     

Combination of Aβ clearance and neurotrophic factors as a potential treatment for Alzheimer’s disease

There is no effective drug to treat Alzheimer’s disease (AD), a neurodegenerative disease affecting an estimated 30 million people around the world. Strongly supported by preclinical and clinical studies, amyloid-beta (Aβ) may be a target for developing drugs against AD. Meanwhile, the fact that localized neuronal death/loss and synaptic impairment occur in AD should also be considered. Neuronal regeneration, which does not occur normally in the mammalian central nervous system, can be promoted by neurotrophic factors (NTFs). Evidence from clinical trials has shown that both Aβ clearance and NTFs are potentially effective in treating AD, thus a new approach combining Aβ clearance and administration of NTFs may be an effective therapeutic strategy.     

Mitochondrial dysfunction and cellular metabolic deficiency in Alzheimer’s disease

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder. The pathology of AD includes amyloid-β (Aβ) deposits in neuritic plaques and neurofibrillary tangles composed of hyperphosphorylated tau, as well as neuronal loss in specific brain regions. Increasing epidemiological and functional neuroimaging evidence indicates that global and regional disruptions in brain metabolism are involved in the pathogenesis of this disease. Aβ precursor protein is cleaved to produce both extracellular and intracellular Aβ, accumulation of which might interfere with the homeostasis of cellular metabolism. Mitochondria are highly dynamic organelles that not only supply the main energy to the cell but also regulate apoptosis. Mitochondrial dysfunction might contribute to Aβ neurotoxicity. In this review, we summarize the pathways ofAβ generation and its potential neurotoxic effects on cellular metabolism and mitochondrial dysfunction.     

The plasminogen activating system in the pathogenesis of Alzheimer’s disease

Dementia is a clinical syndrome that affects approximately 47 million people worldwide and is characterized by progressive and irreversible decline of cognitive,behavioral and sesorimotor functions.Alzheimer’s disease(AD)accounts for approximately 60–80%of all cases of dementia,and neuropathologically is characterized by extracellular deposits of insoluble amyloid-β(Aβ)and intracellular aggregates of hyperphosphorylated tau.Significantly,although for a long time it was believed that the extracellular accumulation of Aβwas the culprit of the symptoms observed in these patients,more recent studies have shown that cognitive decline in people suffering this disease is associated with soluble Aβ-induced synaptic dysfunction instead of the formation of insoluble Aβ-containing extracellular plaques.These observations are translationally relevant because soluble Aβ-induced synaptic dysfunction is an early event in AD that precedes neuronal death,and thus is amenable to therapeutic interventions to prevent cognitive decline before the progression to irreversible brain damage.The plasminogen activating(PA)system is an enzymatic cascade that triggers the degradation of fibrin by catalyzing the conversion of plasminogen into plasmin via two serine proteinases:tissue-type plasminogen activator(tPA)and urokinase-type plasminogen activator(uPA).Experimental evidence reported over the last three decades has shown that tPA and uPA play a role in the pathogenesis of AD.However,these studies have focused on the ability of these plasminogen activators to trigger plasmin-induced cleavage of insoluble Aβ-containing extracellular plaques.In contrast,recent evidence indicates that activity-dependent release of uPA from the presynaptic terminal of cerebral cortical neurons protects the synapse from the deleterious effects of soluble Aβvia a mechanism that does not require plasmin generation or the cleavage of Aβfibrils.Below we discuss the role of the PA system in the pathogenesis of AD and the translational relevance of data published to this date.     

Alzheimer’s disease:a tale of two diseases?

Sporadic late-onset Alzheimer’s disease(SLOAD)and familial early-onset Alzheimer’s disease(FEOAD)associated with dominant mutations in APP,PSEN1 and PSEN2,are thought to represent a spectrum of the same disorder based on near identical behavioral and histopathological features.Hence,FEOAD transgenic mouse models have been used in past decades as a surrogate to study SLOAD pathogenic mechanisms and as the gold standard to validate drugs used in clinical trials.Unfortunately,such research has yielded little output in terms of therapeutics targeting the disease’s development and progression.In this short review,we interrogate the widely accepted view of one,dimorphic disease through the prism of the Bmi1+/–mouse model and the distinct chromatin signatures observed between SLOAD and FEOAD brains.     

Effect of high cholesterol diet on spatial learning and memory in a rat model of Alzheimer’s disease

BACKGROUND: Recently study indicates a potentially important link between cholesterol, Aβ deposit, and clinicopathological manifestation of Alzheimer’s disease (AD). OBJECTIVE: To study the effect of high cholesterol diet on cognitive function and neuronal loss of hippocampal dentate gyrus in AD model rats. DESIGN, TIME AND SETTING: A randomized controlled animal study, which was performed in the Laboratory of Stem Cells, Department of Pathology, Third Military Medical University of Chinese PLA from Februar...     

BACE1 in the retina：a sensitive biomarker for monitoring early pathological changes in Alzheimer’s disease

Because of a lack of sensitive biomarkers,the diagnosis of Alzheimer's disease(AD) cannot be made prior to symptom manifestation.Therefore,it is crucial to identify novel biomarkers for the presymptomatic diagnosis of AD.While brain lesions are a major feature of AD,retinal pathological changes also occur in patients.In this study,we investigated the temporal changes in β-site APP-cleaving enzyme 1(BACE1) expression in the retina and brain to determine whether it could serve as a suitable biomarker for early monitoring of AD.APP/PS-1 transgenic mice,3,6 and 8 months of age,were used as an experimental group,and age-matched C57/BL6 wild-type mice served as the control group.In the Morris water maze test,there were no significant differences in escape latency or in the number of crossings in the target area among mice of different ages.Compared with wild-type mice,no changes in learning or memory abilities were detected in transgenic mice at 3 months of age.However,compared with wild-type mice,the escape latency was significantly increased in transgenic mice at 6 months,starting on day 3,and at 8 months,starting on day 2,during Morris water maze training.In addition,the number of crossings of the target area was significantly decreased in transgenic mice.The learning and memory abilities of transgenic mice were further worsened at 8 months of age.Immunohistochemical staining revealed no BACE1 plaques in wild-type mice at 3,6 or 8 months or in transgenic mice at 3 months,but they were clearly found in the entorhinal cortex,hippocampus and prefrontal cortex of transgenic mice at 6 and 8 months.BACE1 expression was not detected in the retina of wild-type mice at 3 months,but weak BACE1 expression was detected in the ganglion cell layer,inner plexiform layer and outer plexiform layer at 6 and 8 months.In transgenic mice,BACE1 expression in the ganglion cell layer was increased at 3 months,and BACE1 expression in the ganglion cell layer,inner plexiform layer and outer plexiform layer was significantly increased at 6 and 8 months,compared with age-matched wild-type mice.Taken together,these results indicate that changes in BACE1 expression appear earlier in the retina than in the brain and precede behavioral deficits.Our findings suggest that abnormal expression of BACE1 in the retina is an early pathological change in APP/PS-1 transgenic mice,and that BACE1 might have potential as a biomarker for the early diagnosis of AD in humans.     

How close is the stem cell cure to the Alzheimer’s disease Future and beyond?

Alzheimer’s disease, a progressive neurodegenerative illness, is the most common form of dementia. So far, there is neither an effective prevention nor a cure for Alzheimer’s disease. In recent decades, stem cell therapy has been one of the most promising treatments for Alzheimer’s disease patients. This article aims to summarize the current progress in the stem cell treatments for Alzheimer’s disease from an experiment to a clinical research.     

Estrogen receptor beta treats Alzheimer’s disease

In vitro studies have shown that estrogen receptor β can attenuate the cytotoxic effect of amyloid β protein on PC12 cells through the Akt pathway without estrogen stimulation. In this study, we aimed to observe the effect of estrogen receptor β in Alzheimer’s disease rat models established by intraventricular injection of amyloid β protein. Estrogen receptor β lentiviral particles delivered via intraventricular injection increased Akt content in the hippocampus, decreased interleukin-1β mRNA, tumor necrosis factor α mRNA and amyloid β protein levels in the hippocampus, and improved the learning and memory capacities in Alzheimer’s disease rats. Estrogen receptor β short hairpin RNA lentiviral particles delivered via intraventricular injection had none of the above impacts on Alzheimer’s disease rats. These experimental findings indicate that estrogen receptor β, independent from estrogen, can reduce inflammatory reactions and amyloid β deposition in the hippocampus of Alzheimer’s disease rats, and improve learning and memory capacities. This effect may be mediated through activation of the Akt pathway.     

Effect of Daicong solution on hippocampal muscarinic receptors 1 and 3 gene expression in a rat model of Alzheimer’s disease

BACKGROUND: It has been previously shown that the muscarinic (M) receptor is involved in brain arousal and selective attention, mood, and motor coordination. OBJECTIVE: To explore the effects of various intragastric Daicong doses on hippocampal M1 and M3 receptor gene expression in a rat model of Alzheimer’s disease. DESIGN, TIME AND SETTING: A randomized cellular and molecular biology experiment, conducted at the Molecular Immunology Laboratory in Shandong between October 2006 and April 2007. MATERIALS: Fi...     

The choroid plexus-cerebrospinal lfuid interface in Alzheimer’s disease：more than just a barrier

The choroid plexus is a complex structure which hangs inside the ventricles of the brain and consists mainly of choroid plexus epithelial (CPE) cells surrounding fenestrated capillaries. These CPE cells not only form an anatomical barrier, called the blood-cerebrospinal lfuid barrier (BCSFB), but also present an active interface between blood and cerebrospinal lfuid (CSF). CPE cells perform indispensable functions for the development, maintenance and functioning of the brain. Indeed, the primary role of the choroid plexus in the brain is to maintain homeostasis by secreting CSF which contains different molecules, such as nutrients, neurotrophins, and growth factors, as well as by clearing toxic and undesirable molecules from CSF. The choroid plexus also acts as a selective entry gate for leukocytes into the brain. Recent ifndings have revealed distinct changes in CPE cells that are associated with aging and Alzheimer’s disease. In this review, we review some recent ifndings that highlight the importance of the CPE-CSF system in Alzheimer’s dis-ease and we summarize the recent advances in the regeneration of brain tissue through use of CPE cells as a new therapeutic strategy.     

Impairment of the nerve growth factor pathway driving amyloid accumulation in cholinergic neurons the incipit of the Alzheimer's disease story?

The current idea behind brain pathology is that disease is initiated by mild disturbances of common physiological processes. Overtime, the disruption of the neuronal homeostasis will determine irreversible degeneration and neuronal apoptosis. hTis could be also true in the case of nerve growth factor (NGF) al-terations in sporadic Alzheimer’s disease (AD), an age-related pathology characterized by cholinergic loss, amyloid plaques and neurofibrillary tangles. In fact, the pathway activated by NGF, a key neurotrophin for the metabolism of basal forebrain cholinergic neurons (BFCN), is one of the ifrst homeostatic systems affected in prodromal AD. NGF signaling dysfunctions have been thought for decades to occur in AD late stages, as a mere consequence of amyloid-driven disruption of the retrograde axonal transport of neuro-trophins to BFCN. Nowadays, a wealth of knowledge is potentially opening a new scenario: NGF signaling impairment occurs at the onset of AD and correlates better than amyloid load with cognitive decline. hTe recent acceleration in the characterization of anatomical, functional and molecular proifles of early AD is aimed at maximizing the efficacy of existing treatments and setting novel therapies. Accordingly, the elucidation of the molecular events underlying APP metabolism regulation by the NGF pathway in the sep-to-hippocampal system is crucial for the identiifcation of new target molecules to slow and eventually halt mild cognitive impairment (MCI) and its progression toward AD.     

Role of exosomes in the pathogenesis of inflammation in Parkinson’s disease

Inflammatory responses,including glial cell activation and peripheral immune cell infiltration,are involved in the pathogenesis of Parkinson’s disease(PD).These inflammatory responses appear to be closely related to the release of extracellular vesicles,such as exosomes.However,the relationships among different forms of glial cell activation,synuclein dysregulation,mitochondrial dysfunction,and exosomes are complicated.This review discusses the multiple roles played by exosomes in PD-associated inflammation and concludes that exosomes can transport toxicα-synuclein oligomers to immature neurons and into the extracellular environment,inducing the oligomerization ofα-synuclein in normal neurons.Misfoldedα-synuclein causes microglia and astrocytes to activate and secrete exosomes.Glial cell-derived exosomes participate in communications between glial cells and neurons,triggering anti-stress and anti-inflammatory responses,in addition to axon growth.The production and release of mitochondrial vesicles and exosomes establish a new mechanism for linking mitochondrial dysfunction to systemic inflammation associated with PD.Given the relevance of exosomes as mediators of neuron-glia communication in neuroinflammation and neuropathogenesis,new targeted treatment strategies are currently being developed that use these types of extracellular vesicles as drug carriers.Exosome-mediated inflammation may be a promising target for intervention in PD patients.     

The role of synphilin-1 in the pathogenesis of Parkinson’s disease

1 Introduction Parkinson’s disease (PD) is the second most common neurological disorder to affect approximate 0.2% of overall population and 2% of those over the age of 65. The disease is characterized by a triad of cardinal symptoms, including bradykinesia (slowed movement), resting tremor, and rigidity. Progressive degeneration of the dopaminergic (DAergic) neurons which are mostly located in the sub- stantia nigra pars compacta (SNpc), and the formation of eosinophilic inclusions known a…