Orexin increases the neuronal excitability of several brain areas associated with maintaining of arousal.

Orexin is exclusively produced in neurons localized within the lateral hypothalamic area (LHA) and perifornical area (PFA). Orexin has been identified as a key promotor of arousal. The selective loss of orexinergic neurons results in narcolepsy. It is known that the intrinsic electrophysiological properties are critical for neurons to perform their functions in corresponding brain regions. In addition to hypothalamic orexin, other brain nuclei are involved in the regulation of sleep and wakefulness. Quite a lot of studies focus on elucidating orexin-induced regulation of sleep-wake states and modulation of neuronal electrophysiological properties in several brain regions. Here, we summarize that the orexinergic neurons exhibit spontaneous firing activity which is associated with the states of sleep-wake cycle. Orexin mainly exerts postsynaptic excitatory effects on multiple brain nuclei associated with the process of sleep and wakefulness. This review may provide a background to guide future research about the cellular mechanisms of orexin-induced maintaining of arousal.

BMAL1 regulation of microglia-mediated neuroinflammation in MPTP-induced Parkinson's disease mouse model.

Dysfunction of the circadian rhythm is one of most common nonmotor symptoms in Parkinson's disease (PD), but the molecular role of the circadian rhythm in PD is unclear. We here showed that inactivation of brain and muscle ARNT-like 1 (BMAL1) in 1-methyl-4-phenyl-1,2,4,5-tetrahydropyridine (MPTP)-treated mice resulted in obvious motor functional deficit, loss of dopaminergic neurons (DANs) in the substantia nigra pars compacta (SNpc), decrease of dopamine (DA) transmitter, and increased activation of microglia and astrocytes in the striatum. Time on the rotarod or calorie consumption, and food and water intake were reduced in the Bmal1-/- mice after MPTP treatment, suggesting that absence of Bmal1 may exacerbate circadian and PD motor function. We observed a significant reduction of DANs (~35%) in the SNpc, the tyrosine hydroxylase protein level in the striatum (~60%), the DA (~22%), and 3,4-dihydroxyphenylacetic acid content (~29%), respectively, in MPTP-treated Bmal1-/- mice. Loss of Bmal1 aggravated the inflammatory reaction both in vivo and in vitro. These findings suggest that BMAL1 may play an essential role in the survival of DANs and maintain normal function of the DA signaling pathway via regulating microglia-mediated neuroinflammation in the brain.

Disease trajectories in older adults with non-AD pathologic change and comparison with Alzheimer's disease pathophysiology: A longitudinal study.

Based on the 'AT(N)' system, individuals with normal amyloid biomarkers but abnormal tauopathy or neurodegeneration biomarkers are classified as non-Alzheimer's disease (AD) pathologic change. This study aimed to assess the long-term clinical and cognitive trajectories of individuals with non-AD pathologic change among older adults without dementia, comparing them to those with normal AD biomarkers and AD pathophysiology. Analyzing Alzheimer's Disease Neuroimaging Initiative data, we evaluated clinical outcomes and conversion risk longitudinally using mixed effects models and multivariate Cox proportional hazard models. We found that compared to individuals with A-T-N-, those with abnormal tauopathy or neurodegeneration biomarkers (A-T + N-, A-T-N + , and A-T + N + ) had a faster rate of cognitive decline and disease progression. Individuals with A-T + N + had a faster rate of decline than those with A-T + N-. Additionally, in individuals with the same baseline tauopathy and neurodegeneration biomarker status, the presence of baseline amyloid could accelerate cognitive decline and clinical progression. These findings provide a foundation for future studies on non-AD pathologic change and its comparison with AD pathophysiology.

[Association of vitamin D receptor gene polymorphisms with Parkinson disease].

OBJECTIVE: Vitamin D receptor (VDR) has been proposed as a candidate gene for susceptibility to Parkinson's disease (PD). This study was set to assess the association between VDR gene Apa I and Taq I polymorphisms and PD in a Chinese Han population. METHODS: Two hundred and eighty five sporadic PD patients and 285 healthy controls were genotyped for the Apa I and Taq I polymorphisms in VDR gene using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: No significant difference was detected in genotype or allele distribution of both Apa I and Taq I polymorphisms between PD patients and controls (P U+003E 0.05). No TT genotype for Taq I was found in the studied population. For Taq I, the distribution of genotype was significantly different between male PD patients and controls (U+03C7 2=4.187, P=0.032, OR=2.149, 95%CI: 1.011-4.567), and the frequency of T allele was significantly higher in male PD patients than male controls (U+03C7 2=3.867, P=0.036, OR=2.064, 95%CI: 0.989-4.307). CONCLUSION: VDR gene Apa I polymorphisms are not associated with sporadic Parkinson's disease, but Taq I may be a risk factor for male PD.

Associations Between TREML2 Gene Variants and Alzheimer's Disease: Biomarkers, Neuroimage, and Cognition.

BACKGROUND: Recent genetic research identified a protective factor against late-onset Alzheimer's disease (AD) in Caucasians, a variant called rs3747742-C in the TREML2 gene. However, the roles of other TREML2 variants in AD have not been fully explored. OBJECTIVE: We conducted a focused analysis of 16 TREML2 variants, examining their connection to AD by studying their correlation with cerebrospinal fluid (CSF) proteins, neuroimage, and cognition in the Alzheimer's Disease Neuroimaging Initiative database (ADNI). METHODS: A multiple linear regression model was utilized to estimate potential associations between TREML2 genotypes and various endophenotypes in the entire ADNI sample at baseline, with age, gender, years of education, and APOE ɛ4 status included as covariates. To examine changes in clinical outcomes over time, linear mixed-effects models were employed. RESULTS: We found that the SNP rs17328707-A was associated with higher ADNI-VS scores, smaller ventricles, and larger middle temporal volume at baseline. The SNP rs6915083-G was linked to lower CSF t-tau and p-tau levels, and higher CSF Aß levels. The SNP rs9394766-G was associated with a smaller hippocampus and larger ventricles at baseline. In longitudinal cohorts, the rs6915083-G SNP was associated with changes in ADNI-MEM and ADNI-EF scores, as well as the rate of hippocampal and middle temporal atrophy. CONCLUSION: Our findings reveal that TREML2 gene variants have different effects on AD. Two variants are protective, while one may be a risk factor. This enhances our understanding of AD genetics and could guide future research and personalized treatments.

Disease trajectories in elders with suspected non-Alzheimer's pathophysiology and its comparison with Alzheimer's disease pathophysiology: a longitudinal study.

Background: According to the new 'AT(N)' system, those with a normal amyloid biomarker but with abnormal tauopathy or biomarkers of neurodegeneration or neuronal injury, have been labeled suspected non-Alzheimer's pathophysiology (SNAP). We aimed to estimate the long-term clinical and cognitive trajectories of SNAP individuals in non-demented elders and its comparison with individual in the Alzheimer's disease (AD) pathophysiology using 'AT(N)' system. Methods: We included individuals with available baseline cerebrospinal fluid (CSF) Aß (A), CSF phosphorylated tau examination (T) and 18F-uorodeoxyglucose PET or volumetric magnetic resonance imaging (N) from the Alzheimer's Disease Neuroimaging Initiative database. Longitudinal change in clinical outcomes are assessed using linear mixed effects models. Conversion risk from cognitively normal (CN) to cognitively impairment, and conversion from mild cognitive impairment (MCI) to dementia are assessed using multivariate Cox proportional hazard models. Results: Totally, 366 SNAP individuals were included (114 A-T-N-, 154 A-T + N-, 54 A-T-N + and 44 A-T + N+) of whom 178 were CN and 188 were MCI. Compared with A-T-N-, CN elders with A-T + N-, A-T-N + and A-T + N + had a faster rate of ADNI-MEM score decline. Moreover, CN older individuals with A-T + N + also had a faster rate of decline in ADNI-MEM score than those with A-T + N- individuals. MCI patients with A-T + N + had a faster rate of ADNI-MEM and ADNI-EF decline and hippocampal volume loss compared with A-T-N- and A-T + N- profiles. CN older individuals with A-T + N + had an increased risk of conversion to cognitive impairment (CDR-GS ≥ 0.5) compared with A-T + N- and A-T-N-. In MCI patients, A-T + N + also had an increased risk of conversion to dementia compared with A-T + N- and A-T-N-. Compared with A-T + N-, CN elders and MCI patients with A + T + N- and A + T + N + had a faster rate of ADNI-MEM score, ADNI-EF score decline, and hippocampal volume loss. CN individuals with A + T + N + had a faster rate of ADNI-EF score decline compare with A-T + N + individuals. Moreover, MCI patients with A + T + N + also had a faster rate of decline in ADNI-MEM score, ADNI-EF score and hippocampal volume loss than those with A-T + N + individuals. Conclusions: The findings from clinical, imaging and biomarker studies on SNAP, and its comparison with AD pathophysiology offered an important foundation for future studies.

Exploring the links among peripheral immunity, biomarkers, cognition, and neuroimaging in Alzheimer's disease.

INTRODUCTION: We analyzed relationships among peripheral immunity markers, cognition, Alzheimer's disease (AD)-related biomarkers, and neuroimaging to understand peripheral immunity involvement in AD. METHODS: Peripheral immunity markers were assessed in AD, non-AD neurodegenerative disorders, and controls, examining their connections with cognition, AD-related biomarkers, and neuroimaging using multiple regression models. RESULTS: The study included 1579 participants. Higher levels of white blood cell, neutrophil, monocyte, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and lower lymphocyte-to-monocyte ratio (LMR) were associated with cognitive decline and more severe anxiety and depression. The impact of lower LMR, lymphocyte count, and higher NLR on cognitive decline is mediated through cerebrospinal fluid amyloid beta (Aß) levels. Additionally, increased PLR, NLR, and SII were associated with brain atrophy and hippocampal Aß deposition (amyloid positron emission tomography). DISCUSSION: Peripheral immunity markers offer a non-invasive and cost-effective means of studying AD-related pathophysiological changes, providing valuable insights into its pathogenesis and treatment. Highlights: Peripheral immunity markers linked to cognitive decline and anxiety/depression.Low LMR, LYM, and high NLR linked to reduced CSF Aß, impacting cognition.High PLR, NLR, SII associated with brain atrophy and hippocampal Aß deposition.

The mechanism behind activation of the Nod-like receptor family protein 3 inflammasome in Parkinson's disease.

Previous studies have shown that the ATP-P2X4 receptor signaling pathway mediates the activation of the Nod-like receptor family protein 3 (NLRP3) inflammasome. The NLRP3 inflammasome may promote renal interstitial inflammation in diabetic nephropathy. As inflammation also plays an important role in the pathogenesis of Parkinson's disease, we hypothesized that the ATP-P2X4 receptor signaling pathway may activate the NLRP3 inflammasome in Parkinson's disease. A male rat model of Parkinson's disease was induced by stereotactic injection of 6-hydroxydopamine into the pars compacta of the substantia nigra. The P2X4 receptor and the NLRP3 inflammasome (interleukin-1ß and interleukin-18) were activated. Intracerebroventricular injection of the selective P2X4 receptor antagonist 5-(3-bromophenyl)-1,3-dihydro-2H-benzofuro[3,2-e]-1,4-diazepin-2-one (5-BDBD) or knockdown of P2X4 receptor expression by siRNA inhibited the activation of the NLRP3 inflammasome and alleviated dopaminergic neurodegeneration and neuroinflammation. Our results suggest that the ATP-P2X4 receptor signaling pathway mediates NLRP3 inflammasome activation, dopaminergic neurodegeneration, and dopamine levels. These findings reveal a novel role of the ATP-P2X4 axis in the molecular mechanisms underlying Parkinson's disease, thus providing a new target for treatment. This study was approved by the Animal Ethics Committee of Qingdao University, China, on March 5, 2015 (approval No. QYFYWZLL 26119).

Mechanisms of the Ping-wei-san plus herbal decoction against Parkinson's disease: Multiomics analyses.

Introduction: Parkinson's disease is a neurodegenerative disorder involving loss of dopaminergic neurons. Multiple studies implicate the microbiota-gut-brain axis in Parkinson's disease pathophysiology. Ping-wei-san plus Herbal Decoction, a traditional Chinese medicine composition with beneficial effects in Parkinson's disease, may have a complex array of actions. Here we sought to determine whether gut microbiota and metabolic pathways are involved in Ping-wei-san plus herbal therapy for Parkinson's disease and to identify functional pathways to guide research. Methods and results: The model of Parkinson's disease were induced with the rotenone. The Ping-wei-san plus group received the PWP herbal decoction for 90 days, after which all groups were analyzed experimentally. PWP herbal treatment improved motor behavior and emotional performance, balanced gut microbiota, and benefited dietary metabolism. Tandem Mass Tags mass spectrometry identified many differentially expressed proteins (DEPs) in the substantia nigra and duodenum in the PWP group, and these DEPs were enriched in pathways such as those involving cAMP signaling, glutamatergic synapses, dopaminergic synapses, and ribosome-rich functions in the gut. The PWP group showed increases in recombinant tissue inhibitors of metalloproteinase 3, and nucleotide-binding oligomerization domain, leucine rich repeat, and pyrin domain containing proteins 6 in the substantia nigra and decreased parkin, gasdermin D, recombinant tissue inhibitors of metalloproteinase 3, and nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing proteins 6 in the duodenum. Discussion: In conclusion, this study combined gut microbiota, metabolomics, and proteomics to evaluate the mechanism of action of Ping-wei-san plus on Parkinson's disease and revealed that PWP herbal treatment modulated gut microbiota, altered metabolite biological pathways, and affected functional pathway protein expression in Parkinson's disease mice, resulting in therapeutic effects.

GLP-1 Suppresses Feeding Behaviors and Modulates Neuronal Electrophysiological Properties in Multiple Brain Regions.

The glucagon-like peptide-1 (GLP-1) plays important roles in the regulation of food intake and energy metabolism. Peripheral or central GLP-1 suppresses food intake and reduces body weight. The electrophysiological properties of neurons in the mammalian central nervous system reflect the neuronal excitability and the functional organization of the brain. Recent studies focus on elucidating GLP-1-induced suppression of feeding behaviors and modulation of neuronal electrophysiological properties in several brain regions. Here, we summarize that activation of GLP-1 receptor (GLP-1R) suppresses food intake and induces postsynaptic depolarization of membrane potential and/or presynaptic modulation of glutamatergic or GABAergic neurotransmission in brain nuclei located within the medulla oblongata, pons, mesencephalon, diencephalon, and telencephalon. This review may provide a background to guide future research about the cellular mechanisms of GLP-1-induced feeding inhibition.

P2X4 receptor participates in autophagy regulation in Parkinson's disease.

Dysfunctional autophagy often occurs during the development of neurodegenerative diseases, such as Parkinson's disease, Huntington's disease, and Alzheimer's disease. The purinergic P2X4 receptor is an ATP-gated ion channel that is widely expressed in the microglia, astrocytes, and neurons of the central and peripheral nervous systems. P2X4R is involved in the regulation of cellular excitability, synaptic transmission, and neuroinflammation. However, the role played by P2X4R in Parkinson's disease remains poorly understood. Rat models of Parkinson's disease were established by injecting 6-hydroxydopamine into the substantia nigra pars compacta. P2X4R-targeted small interfering RNA (siRNA) was injected into the same area 1 week before injury induction to inhibit the expression of the P2X4 receptor. The results showed that the inhibition of P2X4 receptor expression in Parkinson's disease model rats reduced the rotation behavior induced by apomorphine treatment, increased the latency on the rotarod test, and upregulated the expression of tyrosine hydroxylase, brain-derived neurotrophic factor, LC3-II/LC3-I, Beclin-1, and phosphorylated tropomyosin receptor kinase B (TrkB) in brain tissue, while simultaneously reducing p62 levels. These findings suggest that P2X4 receptor activation might inhibit neuronal autophagy through the regulation of the brain-derived neurotrophic factor/TrkB signaling pathway, leading to dopaminergic neuron damage in the substantia nigra and the further inhibition of P2X4 receptor-mediated autophagy. These results indicate that P2X4 receptor might serve as a potential novel target for the treatment of Parkinson's disease. This study was approved by the Animal Ethics Committee of Affiliated Hospital of Qingdao University (approval No. QYFYWZLL26119) on April 12, 2016.

Association between serum bilirubin concentration and Parkinson's disease: a meta-analysis.

BACKGROUND: The antioxidant effects of bilirubin in Parkinson's disease (PD) have recently gained much attention from the research community. However, results from these studies have been conflicting. This meta-analysis is conducted to assess the relationship between the serum bilirubin concentration and the risk of PD. METHODS: Two reviewers performed a systematic literature search across five databases (MEDLINE, PubMed, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials). The case-control studies regarding bilirubin levels in PD patients published up to April 2020 were included. These studies were subjected to rigorous scrutiny and data extraction to determine the standard mean difference (SMD) and the 95% confidence interval (CI), which were analyzed using the Stata V.12.0 statistical software. RESULTS: A total of eight studies which included 1463 PD cases and 1490 controls were incorporated into our meta-analysis. SMD analysis showed that there was a higher total bilirubin (TBIL) and direct bilirubin (DBIL) levels in PD patients compared with controls (for TBIL, SMD: 0.300, 95% CI: 0.050-0.549, P = 0.018; for DBIL, SMD: 0.395, 95% CI: 0.102-0.688, P = 0.008). However, no significant relationship was found between the serum indirect bilirubin and PD patients (SMD: -0.223, 95% CI: -0.952-0.505, P = 0.548). A subgroup analysis based on ethnicity indicated that the serum TBIL was higher in PD patients of Caucasian descent in contrast to matched healthy controls (SMD: 0.511, 95% CI: 0.324-0.698, P = 0.000, I2 = 58.0%). CONCLUSION: Higher serum bilirubin levels in PD patients suggest that bilirubin might play a role in the pathogenesis of PD and have the potential to be utilized as a biochemical marker for PD diagnosis and treatment.

Sleep deprivation caused a memory defects and emotional changes in a rotenone-based zebrafish model of Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder in the world. Apart from motor deficits, PD reduces patient's quality of life through sleep disturbances, cognitive impairment and emotional disorders. However, it's unclear whether bad life habits such as stay up late exacerbate the patient's cognition and emotional disorders. Thus we investigated the consequences of sleep deprivation (SD) on memory and emotions using a rotenone-based zebrafish model of PD. Behavioral assays, using locomotor activity assay, showed that rotenone treated zebrafish exhibited PD-like symptoms, whereas sleep deprivation didn't exacerbate the progression of them. The object discrimination task exhibited that the short-term cognitive deficits of rotenone group are more serious than the sham group after SD. Light-dark box test showed that rotenone treated fish are more dysphoric than the sham fish after SD. Dopamine and DOPAC significantly reduced in rotenone treated fish compared with the sham fish. However, this DOPAC reduction recovered after SD. The expression of D2 and D3 in rotenone treated zebrafish elevated compared with sham group and SD group. However, the rotenone treated zebrafish manifested a decrease level of D2 and D3 after SD. D1 did not show any significantly changes among the four groups. Our findings suggest that zebrafish treated with rotenone may have a more severe damage of memory and emotional function after SD, which may be related to the changes in the DA systems.

Association of AKT1 gene polymorphisms with sporadic Parkinson's disease in Chinese Han population.

Genetic variants of AKT1 have been shown to influence brain function of Parkinson's disease (PD) patients, and in this paper our aim is to investigate the association between the three single-nucleotide polymorphisms (rs2498799; rs2494732; rs1130214) and PD in Han Chinese. 413 Han Chinese PD patients and 450 healthy age and gender-matched controls were genotyped using the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method. Both the patient and control groups show similar genotype frequencies at the three loci: rs2498799, rs2494732 and rs1130214. We are able to identify a significant difference in the frequencies of genotype (p=0.019) and G allele (OR=0.764, 95% CI=0.587-0.995, p=0.045) both at rs2498799 between the patient and control groups. Furthermore, the association of subjects with GG genotypes versus those with GA+AA genotype remain significant after adjusting for age in the Han Chinese female cohort (OR=0.538, 95%CI=0.345-0.841, p=0.006), which is especially evident in the late-onset cohort (OR=0.521, 95%CI=0.309-0.877, p=0.012). In contrast, allele frequencies at rs2494732 and rs1130214 were similar between patients and controls in all subgroup analyses. These results suggest that polymorphism of AKT1 locus is associated with risk of PD and that the G allele at rs2498799 may decrease the risk of PD in the North-eastern part of Han Chinese female population.

The Role of Reelin Signaling in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common causes of age-related dementia. It is characterized by the deposition of amyloid-beta peptide and neurofibrillary tangles, as well as neuronal death and synaptic loss. Reelin is an extracellular glycoprotein which performs diverse roles in the developing and adult brain, including regulation of neuronal migration, dendritogenesis, synapse development, hippocampal synaptic plasticity, and learning and memory. Altered expression and glycosylation patterns of Reelin in cerebrospinal and cortical extracts have been reported in AD. Accumulating studies have investigated the molecular mechanism by which Reelin, its receptors, and downstream signaling proteins may contribute to the pathophysiology of AD. However, the molecular mechanisms by which Reelin and its downstream signal transduction contribute to the pathogenesis of AD remain still largely unknown. In the present review, we briefly summarize the current knowledge and recent findings related to the molecular link between Reelin dysfunction and AD-related neuropathology.

[Effect of the oil from ganoderma lucidum spores on pathological changes in the substantia nigra and behaviors of MPTP-treated mice].

OBJECTIVE: To investigate the oil from the spores of ganoderma lucidum, a rare Chinese herb, on the behaviors and pathological changes in the substantia nigra pars compacta (SNpc) in mouse models of Parkinson's disease (PD) induced by MPTP. METHODS: C57BL mice were divided into 3 groups, and the ganoderma spores oil + MPTP group were treated with ganoderma spores oil for 8 days, together with subcutaneous injection of MPTP (30 mg/kg) starting on the third day for 6 days; MPTP group were pretreated with normal saline before subcutaneous MPTP injection, and the normal control group received pretreatment with normal saline before subcutaneous normal saline injection. The behavioral changes of the mice in different groups were observed by pole test, dopamine and its metabolic products in the striatum determined by HPLC, tyrosine hydroxylase (TH) positive cells detected by immunofluorescence method, and expression of TH protein by Western blotting. RESULTS: The mice in the ganoderma spores oil + MPTP group presented significantly less involuntary movement of the limbs in the pole test than the mice in MPTP group. The levels of dopamine and DOPAC in the striatum of ganoderma spores oil-treated mice were increased as compared with those in MPTP group. The number of surviving TH-positive neurons in SNpc of mice in ganoderma spores oil + MPTP group was significantly greater than that in MPTP group, with also significantly increased TH protein expression. CONCLUSION: Ganoderma spores oil has neuroprotective effect for preventing doparminergic neuron from impairment by MPTP.

ApaI, BsmI, FokI, and TaqI Polymorphisms in the Vitamin D Receptor Gene and Parkinson's Disease.

BACKGROUND: The vitamin D receptor (VDR) gene has been identified as a candidate gene for susceptibility to Parkinson's disease (PD), but results from genetic association studies to date are inconsistent. Here, we conducted a meta-analysis of published case-control studies to evaluate the association of the extensively studied VDR ApaI (G/T), BsmI (G/A), FokI (C/T), and TaqI (T/C) gene polymorphisms with risk of PD. METHODS: Electronic search at PubMed, EMBASE, EBSCO, China National Knowledge Infrastructure, Weipu database, and Wanfang database was conducted to identify all relevant studies. Odds ratio (OR) with 95% confidence interval (CI) values was applied to evaluate the strength of the association. RESULTS: A total of seven studies with 2034 PD cases and 2432 controls were included in the meta-analysis following the inclusion and exclusion criteria. Overall, no significant association between ApaI, BsmI, and TaqI gene polymorphisms and PD susceptibility in all four genetic models was found (T vs. G: OR = 1.00, 95% CI: 0.89-1.12, P = 0.97; A vs. G: OR = 0.94, 95% CI: 0.77-1.15, P = 0.53; C vs. T: OR = 1.03, 95% CI: 0.85-1.25, P = 0.77) while a significant association between FokI (C/T) and PD risk was observed (C vs. T: OR = 1.41, 95% CI: 1.14-1.75, P = 0.001; CC vs. TT: OR = 2.45, 95% CI: 1.52-3.93, P = 0.0002; CT vs. TT: OR = 2.21, 95% CI: 1.38-3.52, P = 0.0009, CC vs. CT+TT: OR = 2.32, 95% CI: 1.49-3.61, P = 0.0002). CONCLUSIONS: Polymorphisms of ApaI, BsmI, and TaqI may not be associated with the susceptibility to PD while the FokI (C/T) polymorphism is possibly associated with increased PD risk. However, conclusions should be cautiously interpreted due to the relatively small number of studies included.

Heat shock protein 90 in Alzheimer's disease.

Alzheimer's disease (AD) is the first most common neurodegenerative disease. Despite a large amount of research, the pathogenetic mechanism of AD has not yet been clarified. The two hallmarks of the pathology of AD are the extracellular senile plaques (SPs) of aggregated amyloid-beta (Aß) peptide and the accumulation of the intracellular microtubule-associated protein tau into fibrillar aggregates. Heat shock proteins (HSPs) play a key role in preventing protein misfolding and aggregation, and Hsp90 can be viewed as a ubiquitous molecular chaperone potentially involved in AD pathogenesis. A role of Hsp90 regulates the activity of the transcription factor heat shock factor-1 (HSF-1), the master regulator of the heat shock response. In AD, Hsp90 inhibitors may redirect neuronal aggregate formation, and protect against protein toxicity by activation of HSF-1 and the subsequent induction of heat shock proteins, such as Hsp70. Therefore, we review here to further discuss the recent advances and challenges in targeting Hsp90 for AD therapy.

Heat shock protein 70 in Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease that caused dementia which has no effective treatment. Growing evidence has demonstrated that AD is a "protein misfolding disorder" that exhibits common features of misfolded, aggregation-prone proteins and selective cell loss in the mature nervous system. Heat shock protein 70 (HSP70) attracts extensive attention worldwide, because it plays a crucial role in preventing protein misfolding and inhibiting aggregation and represents a class of proteins potentially involved in AD pathogenesis. Numerous studies have indicated that HSP70 could suppress the progression of AD with in vitro and in vivo experiments. Thus, targeting HSP70 and the related compounds might represent a promising strategy for the treatment of AD.

Alteration of mitochondrial function and ultrastructure in the hippocampus of pilocarpine-treated rat.

Present studies were carried out to decipher seizure-dependent changes in mitochondrial function and ultrastructure in rat hippocampus after status epilepticus (SE) induced by pilocarpine (PILO). Discernible mitochondrial ultrastructural damage was observed in the hippocampus. Enzyme assay revealed cytochrome oxidase (COX) activity significantly increased 3h after SE, decreased 7 d and 45 d after SE, whereas succinate dehydrogenase (SDH) activity displayed no significant changes. Quantitative real-time PCR and Western blotting showed that COX III (mitochondrial-encoded) mRNA and protein level were significantly increased at 3h, decreased to the control level on 7d and dropped significantly on 45 d; the corresponding expression of COX IV were not changed by PILO at any time tested. The results were also supported by immunohistochemistry. Thus, our results demonstrate that dysfunction of mitochondrial complex IV respiratory enzyme and mitochondrial ultrastructural damage in the hippocampus are associated with prolonged seizure during experimental temporal lobe epilepsy and mitochondria are more vulnerable to epileptic damage.