Promises and pitfalls of immune-based strategies for Huntington's disease

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disease characterized by the selec-tive loss of neurons in the striatum and cortex, leading to progressive motor dysfunction, cognitive decline and behavioral symptoms. HD is caused by a trinucleotide (CAG) repeat expansion in the gene encoding for huntingtin. Several studies have suggested that inflammation is an important feature of HD and it is already observed in the early stages of the disease. Recently, new molecules presenting anti-inflammatory and/or immunomodulatory have been investigated for HD. The objective of this review is to discuss the data obtained so far on the immune-based therapeutic strategies for HD.     

TLR2 and TLR4-mediated inflammation in Alzheimer's disease: self-defense or sabotage?

正Alzheimer's disease(AD) is an irreversible disease that leads to neurodegeneration.The underpinning mechanisms of neuronal cell death are a matter of ongoing debate regarding the impact of accumulation of the amyloid beta(Aβ)peptide and post-translation modifications of the tau protein.However,a growing area of research and one that may provide a more rigorous account of the early changes seen in Alzheimer's brains is inflammation.     

Genistein protects hippocampal neurons against injury by regulating calcium/calmodulin dependent protein kinase Ⅳ protein levels in Alzheimer's disease model rats

Genistein has a neuroprotective effect in Alzheimer's disease, but its mechanism of action needs further clarification. Accumulating evidence suggests that excessive phosphorylation of tau protein causes production of neurofibrillary tangles, which is one of the main pathological characteristics of Alzheimer's disease, and tau protein can be phosphorylated by calcium/calmodulin dependent protein kinase IV(CAMK4). After 7 days of pre-administration of genistein(90 mg/kg), an Alzheimer's disease rat model was established using an intraperitoneal injection of D-galactose combined with an intracerebral injection of amyloid-β peptide(25–35). The rat was then continuously administered genistein(90 mg/kg) for 42 days. The Morris water maze test, western blotting and hematoxylin-eosin staining results showed that genistein significantly decreased the escape latency and increased the number of times crossing the platform, reduced p-tau, CALM, CAMKK1 and p-CAMK4 protein levels in the hippocampus, and alleviated hippocampal neuron damage. These findings indicate that genistein may play a neuroprotective role in Alzheimer's disease through regulating CAMK4 to modulate tau hyperphosphorylation.     

Genistein protects hippocampal neurons against injury by regulating calcium/calmodulin dependent protein kinase IV protein levels in Alzheimer's disease model rats

Genistein has a neuroprotective effect in Alzheimer's disease, but its mechanism of action needs further clarification. Accumulating evidence suggests that excessive phosphorylation of tau protein causes production of neurofibrillary tangles, which is one of the main pathological characteristics of Alzheimer's disease, and tau protein can be phosphorylated by calcium/calmodulin dependent protein kinase IV (CAMK4). After 7 days of pre-administration of genistein (90 mg/kg), an Alzheimer's disease rat model was established using an intraperitoneal injection of D-galactose combined with an intracerebral injection of amyloid-β peptide (25–35). The rat was then continu-ously administered genistein (90 mg/kg) for 42 days. The Morris water maze test, western blotting and hematoxylin-eosin staining results showed that genistein significantly decreased the escape latency and increased the number of times crossing the platform, reduced p-tau, CALM, CAMKK1 and p-CAMK4 protein levels in the hippocampus, and alleviated hippocampal neuron damage. These findings indicate that genistein may play a neuroprotective role in Alzheimer's disease through regulating CAMK4 to modulate tau hyperphosphorylation.     

Using Huntingtin Knock-In Minipigs to Fill the Gap Between Mouse Models and Patients with Huntington’s Disease

正Huntington’s disease (HD) is an inherited autosomal dominant neurodegenerative disease characterized by progressive motor deficits, cognitive decline, and psychiatric symptoms. It is caused by a pathological expansion of CAG trinucleotide repeats in exon 1 of the HD gene,resulting in the translation of a mutant form of huntingtin     

Autophagy and its neuroprotection in neurodegenerative diseases

It has been suggested that protein misfolding and aggregation contribute significantly to the development of neurodegenerative diseases.Misfolded and aggregated proteins are cleared by ubiquitin proteasomal system (UPS) and by both Micro and Macro autophagy lysosomal pathway (ALP).Autophagosomal dysfunction has been implicated in an increasing number of diseases including neurodegenerative diseases.Autophagy is a cellular self-eating process that plays an important role in neuroprotection as well as neuronal injury and death.While a decrease in autophagic activity interferes with protein degradation and possibly organelle turnover,increased autophagy has been shown to facilitate the clearance of aggregation-prone proteins and promote neuronal survival in a number of disease models.On the other hand,too much autophagic activity can be detrimental,suggesting the regulation of autophagy is critical in dictating cell fate.In this review paper,we will discuss various aspects of ALP biology and its dual functions in neuronal cell death and survival.We will also evaluate the role of autophagy in neurodegenerative diseases including Alzheimer’s disease,Parkinson’s disease,Huntington’s disease,amyotrophic lateral sclerosis.Finally,we will explore the therapeutic potential of autophagy modifiers in several neurodegenerative diseases.     

Divalent cation tolerance protein binds to β-secretase and inhibits the processing of amyloid precursor protein

The deposition of amyloid-beta is a pathological hallmark of Alzheimer’s disease. Amyloid-beta is derived from amyloid precursor protein through sequential proteolytic cleavages by β-secretase (beta-site amyloid precursor protein-cleaving enzyme 1) and γ-secretase. To further elucidate the roles of beta-site amyloid precursor protein-cleaving enzyme 1 in the development of Alzheimer’s disease, a yeast two-hybrid system was used to screen a human embryonic brain cDNA library for proteins directly interacting with the intracellular domain of beta-site amyloid precursor protein-cleaving enzyme 1. A potential beta-site amyloid precursor protein-cleaving enzyme 1- interacting protein identified from the positive clones was divalent cation tolerance protein. Immunoprecipitation studies in the neuroblastoma cell line N2a showed that exogenous divalent cation tolerance protein interacts with endogenous beta-site amyloid precursor protein-cleaving enzyme 1. The overexpression of divalent cation tolerance protein did not affect beta-site amyloid precursor protein-cleaving enzyme 1 protein levels, but led to increased amyloid precursor protein levels in N2a/APP695 cells, with a concomitant reduction in the processing product amyloid precursor protein C-terminal fragment, indicating that divalent cation tolerance protein inhibits the processing of amyloid precursor protein. Our experimental findings suggest that divalent cation tolerance protein negatively regulates the function of beta-site amyloid precursor protein-cleaving enzyme 1. Thus, divalent cation tolerance protein could play a protective role in Alzheimer’s disease.     

Glyco-sphingo biology: a novel perspective for potential new treatments in Huntington's disease

<正>Huntington’s disease(HD)is the most common dominantly inherited neurodegenerative disorder,mainly characterized by the progressive striatal and cortical neurodegeneration and associated motor,cognitive and behavioural disturbances(Zuccato et al.,2010).The disease-causing mutation is an expansion of a CAG trinucleotide repeat(36 repeats)encoding a polyglutamine stretch in the N-terminal region of huntingtin(Htt)(Zuccato et al.,2010),a ubiquitous protein whose function is still     

Toxic tau: structural origins of tau aggregation in Alzheimer's disease

Alzheimer’s disease is characterized by the extracellular accumulation of the amyloidβin the form of amyloid plaques and the intracellular deposition of the microtubule-associated protein tau in the form of neurofibrillary tangles.Most of the Alzheimer’s drugs targeting amyloidβhave been failed in clinical trials.Particularly,tau pathology connects greatly in the pathogenesis of Alzheimer’s disease.Tau protein enhances the stabilization of microtubules that leads to the appropriate function of the neuron.Changes in the quantity or the conformation of tau protein could affect its function as a microtubules stabilizer and some of the processes wherein it is involved.The molecular mechanisms leading to the accumulation of tau are principally signified by numerous posttranslational modifications that change its conformation and structural state.Therefore,aberrant phosphorylation,as well as truncation of tau protein,has come into focus as significant mechanisms that make tau protein in a pathological entity.Furthermore,the shape-shifting nature of tau advocates to comprehend the progression of Alzheimer’s disease precisely.In this review,we emphasize the recent studies about the toxic and shape-shifting nature of tau in the pathogenesis of Alzheimer’s disease.     

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

Parkinson＇s disease （PD） is one of the commonest neurodegenerative disorders characterized by the loss of dopaminergic （DAergic） neurons in the substantia nigra and the appearance of Lewy bodies （LBs）, whose cytoplasmic inclusions are highly enriched with ubiquitin, synphilin- 1, α-synuclein and park：in. Synphilin- 1 is an α-synuclein-binding protein and a major component of LBs, It is widely accepted that synphilin- 1 is involved in the pathogenic process of PD. This review will provide an overall view of the role of synphilin- 1 in the pathogenesis of Parkinson＇ s disease and the latest findings in this field.     

Could autophagy dysregulation link neurotropic viruses to Alzheimer's disease?

Neurotropic herpesviruses have been associated with the onset and progression of Alzheimer's disease, a common form of dementia that afflicts a large percentage of elderly individuals. Interestingly, among the neurotropic herpesviruses, herpes simplex virus-1, human herpesvirus-6 A, and human herpesvirus-6B have been reported to infect several cell types present in the central nervous system and to dysregulate autophagy, a process required for homeostasis of cells, especially neurons. Indeed autophagosome accumulation, indicating an unbalance between autophagosome formation and autophagosome degradation,has been observed in neurons of Alzheimer's disease patients and may play a role in the intracellular and extracellular accumulation of amyloid β and in the altered protein tau metabolism. Moreover, herpesvirus infection of central nervous system cells such as glia and microglia can increase the production of oxidant species through the alteration of mitochondrial dynamics and promote inflammation, another hallmark of Alzheimer's disease. This evidence suggests that it is worth further investigating the role of neurotropic herpesviruses, particularly human herpesvirus-6A/B, in the etiopathogenesis of Alzheimer's disease.     

The role of DJ-1 complexes and catecholamine metabolism: relevance for familial and idiopathic Parkinson's disease

正Autosomal recessive mutations in the PARK7 gene,which encodes for the protein DJ-1,result in a loss of function and are a cause of familial Parkinson’s disease(PD),while increased wild-type DJ-1protein levels are associated with some forms of cancer.Several functions of DJ-1 have been described,with the greatest evidence indicating that DJ-1 is a redox-sensitive protein involved in the regulation of oxidative stress and cell survival.We have recently reported that the     

Factors contributing to clinical picture and progression of Huntington's disease

正Huntington’s disease(HD)is an autosomal dominant,monogenic,progressive,neurodegenerative and rare disease with a frequency of10 per 100,000 in the Caucasian population and occurring more rarely in other races(Squitieri et al.,1994).HD is,nevertheless,one of the most frequently and extensively studied diseases of those caused by a dynamic mutation.The HD mutation is located on the short arm of the 4th chromosome within the HTT gene.This mutation consists of cytidine,adenosine and guanosine(…CAG CAG CAG…),namely     

Early Activation of Astrocytes does not Affect Amyloid Plaque Load in an Animal Model of Alzheimer’s Disease

Astrocytes are closely associated with Alzheimer's disease(AD). However, their precise roles in AD pathogenesis remain controversial. One of the reasons behind the different results reported by different groups might be that astrocytes were targeted at different stages of disease progression. In this study, by crossing h APP(human amyloid precursor protein)-J20 mice with a line of GFAP-TK mice, we found that astrocytes were activated specifically at an early stage of AD before the occurrence of amyloid plaques, while microglia were not affected by this crossing. Activation of astrocytes at the age of 3–5 months did not affect the proteolytic processing of hAPP and amyloid plaque loads in the brains of hAPP-J20 mice. Our data suggest that early activation of astrocytes does not affect the deposition of amyloid b in an animal model of AD.     

Phosphatidylserine improves axonal transport by inhibition of HDAC and has potential in treatment of neurodegenerative diseases

Familial dysautonomia (FD) is a rare children neurodegenerative disease caused due to a point mutation in the IKBKAP gene that results in decreased IKK complex-associated protein (IKAP) protein production. The disease affects mostly the dorsal root ganglion (DRG) and the sympathetic ganglion. Recently, we found that the molecular mechanisms underlying neurodegeneration in FD patients are defects in axonal transport of nerve growth factors and microtubule stability in the DRG. Neurons are highly polarized cells with very long axons. In order to survive and maintain proper function, neurons depend on transport of proteins and other cellular components from the neuronal body along the axons. We further demonstrated that IKAP is necessary for axon maintenance and showed that phosphatidylserine acts as an HDAC6 inhibitor to rescue neuronal function in FD cells. In this review, we will highlight our latest research findings.     

Verbascoside promotes the regeneration of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra

Tyrosine hydroxylase is a key enzyme in dopamine biosynthesis. Change in tyrosine hydroxylase expression in the nigrostriatal system is closely related to the occurrence and development of Parkinson’s disease. Verbascoside, an extract from Radix Rehmanniae Praeparata has been shown to be clinically effective in treating Parkinson’s disease. However, the underlying mechanisms remain unclear. It is hypothesized that the effects of verbascoside on Parkinson’s disease are related to tyrosine hydroxylase expression change in the nigrostriatal system. Rat models of Parkinson’s disease were established and verbascoside (60 mg/kg) was administered intraperitoneally once a day. After 6 weeks of verbascoside treatment, rat rotational behavior was alleviated; tyrosine hydroxylase mRNA and protein expression and the number of tyrosine hydroxylase-immunoreactive neurons in the rat right substantia nigra were signiifcantly higher than the Parkinson’s model group. These ifndings suggest that the mechanism by which verbascoside treats Parkinson’s disease is related to the regeneration of tyrosine hy-droxylase-immunoreactive neurons in the substantia nigra.     

Synaptic dysfunction in Alzheimer's disease:the effects of amyloid beta on synaptic vesicle dynamics as a novel target for therapeutic intervention

The most prevalent form of dementia in the elderly is Alzheimer's disease.A significant contributing factor to the progression of the disease appears to be the progressive accumulation of amyloid-β42(Aβ42),a small hydrophobic peptide.Unfortunately,attempts to develop therapies targeting the accumulation of Aβ42 have not been successful to treat or even slow down the disease.It is possible that this failure is an indication that targeting downstream effects rather than the accumulation of the peptide itself might be a more effective approach.The accumulation of Aβ42 seems to affect various aspects of physiological cell functions.In this review,we provide an overview of the evidence that implicates Aβ42 in synaptic dysfunction,with a focus on how it contributes to defects in synaptic vesicle dynamics and neurotransmitter release.We discuss data that provide new insights on the Aβ42 induced pathology of Alzheimer's disease and a more detailed understanding of its contribution to the synaptic deficiencies that are associated with the early stages of the disease.Although the precise mechanisms that trigger synaptic dysfunction are still under investigation,the available data so far has enabled us to put forward a model that could be used as a guide to generate new therapeutic targets for pharmaceutical intervention.