Corticothalamic input derived from corticospinal neurons contributes to chronic neuropathic pain after spinal cord injury.

Neuropathic pain is a significant and persistent issue for individuals with spinal cord injuries (SCI), severely impacting their quality of life. While changes at the peripheral and spinal levels are known to contribute to SCI-related pain, whether and how supraspinal centers contribute to post SCI chronic neuropathic pain is poorly understood. Here, we first validated delayed development of chronic neuropathic pain in mice with moderate contusion SCI. To identify supraspinal regions involved in the pathology of neuropathic pain after SCI, we next performed an activity dependent genetic screening and identified multiple cortical and subcortical regions that were activated by innocuous tactile stimuli at a late stage following contusion SCI. Notably, chemogenetic inactivation of pain trapped neurons in the lateral thalamus alleviated neuropathic pain and reduced tactile stimuli evoked cortical overactivation. Retrograde tracing showed that contusion SCI led to enhanced corticothalamic axonal sprouting and over-activation of corticospinal neurons. Mechanistically, ablation or silencing of corticospinal neurons prevented the establishment or maintenance of chronic neuropathic pain following contusion SCI. These results highlighted a corticospinal-lateral thalamic feed-forward loop whose activation is required for the development and maintenance of chronic neuropathic pain after SCI. Our data thus shed lights into the central mechanisms underlying chronic neuropathic pain associated with SCI and the development of novel therapeutic avenues to treat refractory pain caused by traumatic brain or spinal cord injuries.

Temperature control can abolish anesthesia-induced tau hyperphosphorylation and partly reverse anesthesia-induced cognitive impairment in old mice.

AIMS: Anesthesia is related to cognitive impairment and the risk for Alzheimer's disease. Hypothermia during anesthesia can lead to abnormal hyperphosphorylation of tau, which has been speculated to be involved in anesthesia-induced cognitive impairment. The aim of this study was to investigate whether maintenance of the tau phosphorylation level by body temperature control during anesthesia could reverse the cognitive dysfunction in C57BL/6 mice. METHODS: Eighteen-month-old mice were repeatedly anesthetized during a 2-week period with or without maintenance of body temperature, control mice were treated with normal saline instead of anesthetics. Tau phosphorylation level in mice brain was detected on western blot, and cognitive performance was measured using the Morris water maze (MWM). RESULTS: After anesthesia-induced hypothermia in old mice, tau was hyperphosphorylated and the cognitive performance, measured on MWM, was impaired. When body temperature was controlled during anesthesia, however, the tau hyperphosphorylation was completely avoided, and there was partial recovery in cognitive impairment measured on the MWM. CONCLUSION: Hyperphosphorylation of tau in the brain after anesthesia is an important event, and it might be, although not solely, responsible for postoperative cognitive decline.

Clinical and genetic characteristics in a central-southern Chinese cohort of early-onset Alzheimer's disease.

Background: Mutations in the presenilin-1 (PSEN1), presenilin-2 (PSEN2), and amyloid precursor protein (APP) genes have been commonly identified in early-onset Alzheimer's disease (EOAD). Some of the mutations in the three causative genes, especially the PSEN1 gene, result in variable phenotypes and exhibit clinical heterogeneity among EOAD families. Methods: Using next-generation sequencing (NGS), we performed genetic screening in a Chinese cohort of 18 patients with EOAD, consisting of five familial EOAD and 13 sporadic cases. Results: We identified two likely pathogenic PSEN1 mutations (one novel) and a novel APP mutation in three cases of EOAD, where two are familial and one is sporadic, respectively. In addition, we detected a few variants of uncertain significance (VUS) in several genes, including not only the two known variants in PSEN2 (p.H169N and p.V214L) but also genes causal of other types of dementia or previously identified as risk factors for AD, suggesting the possible involvement of multiple genes in the etiopathology of AD. The patients carrying PSEN1 mutations had an earlier mean age at the onset than those with PSEN2 or APP variants. The initial symptoms varied greatly among patients in the EOAD cohort, from progressive memory impairment and epilepsy to uncommon motor symptoms such as involuntary tremors in the upper extremities. Conclusions: In conclusion, our study provides further evidence of the genetic profile of patients with EOAD from China and expands the mutation spectrum of both PSEN1 and APP. In addition, our results highlight the clinical heterogeneity in patients with EOAD and mutations in PSEN1, PSEN2, and APP and suggest strong effects of genetic variants on clinical phenotypes. Future functional studies are needed to clarify the interaction between AD-causative gene mutations and phenotypic heterogeneity.

Characterizing Early-Onset Alzheimer Disease Using Multiprobe PET/MRI: An AT(N) Framework-Based Study.

PURPOSE: Early-onset Alzheimer disease (EOAD) is rare, highly heterogeneous, and associated with poor prognosis. This AT(N) Framework-based study aimed to compare multiprobe PET/MRI findings between EOAD and late-onset Alzheimer disease (LOAD) patients and explore potential imaging biomarkers for characterizing EOAD. METHODS: Patients with AD who underwent PET/MRI in our PET center were retrospectively reviewed and grouped according to the age at disease onset: EOAD, younger than 60 years; and LOAD, 60 years or older. Clinical characteristics were recorded. All study patients had positive ß-amyloid PET imaging; some patients also underwent 18 F-FDG and 18 F-florzolotau PET. Imaging of the EOAD and LOAD groups was compared using region-of-interest and voxel-based analysis. Correlation of onset age and regional SUV ratios were also evaluated. RESULTS: One hundred thirty-three patients were analyzed (75 EOAD and 58 LOAD patients). Sex ( P = 0.515) and education ( P = 0.412) did not significantly differ between groups. Mini-Mental State Examination score was significantly lower in the EOAD group (14.32 ± 6.74 vs 18.67 ± 7.20, P = 0.004). ß-Amyloid deposition did not significantly differ between groups. Glucose metabolism in the frontal, parietal, precuneus, temporal, occipital lobe, and supramarginal and angular gyri was significantly lower in the EOAD group (n = 49) than in the LOAD group (n = 44). In voxel-based morphometry analysis, right posterior cingulate/precuneus atrophy was more obvious in the EOAD ( P < 0.001), although no voxel survived family-wise error correction. Tau deposition in the precuneus, parietal lobe, and angular, supramarginal, and right middle frontal gyri was significantly higher in the EOAD group (n = 18) than in the LOAD group (n = 13). CONCLUSIONS: Multiprobe PET/MRI showed that tau burden and neuronal damage are more severe in EOAD than in LOAD. Multiprobe PET/MRI may be useful to assess the pathologic characteristics of EOAD.

Human tau may modify glucocorticoids-mediated regulation of cAMP-dependent kinase and phosphorylated cAMP response element binding protein.

Phosphorylation of the cAMP response element binding protein (CREB) by cAMP-dependent kinase (PKA) is critical to memory formation. However, activation of PKA can also increase tau phosphorylation, which may contribute to memory impairment. Therefore, the regulation of PKA may be part of the mechanism by which glucocorticoids (GCs) influence memory. Additionally, the cellular response to GCs may be affected by the presence of human tau. The goal of this paper was to study GCs-mediated regulation of PKA as well as CREB and tau phosphorylation in wild-type HEK293 cells and HEK293 cells stably expressing human tau441 (HEK293/tau441 cells). By using dexamethasone (DEX) as GCs, we found that DEX induced a tau-dependent selective decrease in the level of PKA RIIß subunit protein. The observed decrease in RIIß expression was not due to alterations of mRNA levels and was reversed by inhibiting the proteasome with lactacystin. Moreover, the decrease in RIIß did not diminish the co-localization of the catalytic subunit of PKA with tau and might contribute to the DEX-induced increase in tau phosphorylation at Ser-214. DEX also induced a tau-dependent decrease in CREB phosphorylation that could not be reversed by activating PKA with forskolin. Taken together, these results show that human tau protein may alter the GCs-mediated regulation of PKA activity and CREB phosphorylation.

Global cognitive effects of second-generation antidepressants in patients with Alzheimer's disease: A systematic review and meta-analysis of randomized controlled trials.

The second-generation antidepressants (SGAs) are used widely in patients with Alzheimer's disease (AD) for the treatment of mood disorder, sleep disturbance and psychiatric symptoms. Several evidences from AD mice confirmed that antidepressants could delaying cognitive decline. However, the conclusions varied in randomized controlled trials (RCTs) based on patients. This meta-analysis summarizes the cognitive impact of SGAs on AD patients with different neuropsychiatric symptoms (NPS). Results show there is no effect on cognition and depression between SGAs treatment and controls, and this remains in subgroups analyses of duration of medication (<12 weeks or ≥12 weeks), drug classes (SSRIs or non-SSRIs), combination with anti-dementia medication, various NPS, and degree of AD. The available evidence provides no support for the efficacy of SGAs for cognition and depression of AD patients. The implications of the findings and their mechanism relevance are also discussed in this paper.

18F-APN-1607 Tau Positron Emission Tomography Imaging for Evaluating Disease Progression in Alzheimer's Disease.

PURPOSE: 18F-APN-1607 is a novel tau positron emission tomography (PET) tracer characterized with high binding affinity for 3- and 4-repeat tau deposits. The aim was to analyze the spatial distribution of 18F-APN-1607 PET imaging in Alzheimer's disease (AD) subjects with different stages and to investigate the relationship between the change of tau deposition and overall disease progression. METHODS: We retrospectively analyzed the 18F-APN-1607 PET imaging of 31 subjects with clinically and imaging defined as AD. According to the Mini-Mental State Examination (MMSE) score, patients were divided into three groups, namely, mild (≥21, n = 7), moderate (10-20, n = 16), and severe (≤9, n = 8). PET imaging was segmented to 70 regions of interest (ROIs) and extracted the standard uptake value (SUV) of each ROI. SUV ratio (SUVR) was calculated from the ratio of SUV in different brain regions to the cerebellar cortex. The regions were defined as positive and negative with unsupervised cluster analysis according to SUVR. The SUVRs of each region were compared among groups with the one-way ANOVA or Kruskal-Wallis H test. Furthermore, the correlations between MMSE score and regional SUVR were calculated with Pearson or Spearman correlation analysis. RESULTS: There were no significant differences among groups in gender (χ2 = 3.814, P = 0.161), age of onset (P = 0.170), age (P = 0.109), and education level (P = 0.065). With the disease progression, the 18F-APN-1607 PET imaging showed the spread of tau deposition from the hippocampus, posterior cingulate gyrus (PCG), and lateral temporal cortex (LTC) to the parietal and occipital lobes, and finally to the frontal lobe. Between the mild and moderate groups, the main brain areas with significant differences in 18F-APN-1607 uptake were supplementary motor area (SMA), cuneus, precuneus, occipital lobule, paracentral lobule, right angular gyrus, and parietal, which could be used for early disease progression assessment (P < 0.05). There were significant differences in the frontal lobe, right temporal lobe, and fusiform gyrus between the moderate and severe groups, which might be suitable for the late-stage disease progression assessment (P < 0.05). CONCLUSION: 18F-APN-1607 PET may serve as an effective imaging marker for visualizing the change pattern of tau protein deposition in AD patients, and its uptake level in certain brain regions is closely related to the severity of cognitive impairment. These indicate the potential of 18F-APN-1607 PET for the in vivo evaluation of the progression of AD.

ß-arrestin 2 regulates Toll-like receptor 4-mediated apoptotic signalling through glycogen synthase kinase-3ß.

Toll-like receptor 4 (TLR4), a key member of the TLR family, has been well characterized by its function in the induction of inflammatory products of innate immunity. However, the involvement of TLR4 in a variety of apoptotic events by an unknown mechanism has been the focus of great interest. Our investigation found that TLR4 promoted apoptotic signalling by affecting the glycogen synthase kinase-3beta (GSK-3beta) pathway in a serum-deprivation-induced apoptotic paradigm. Serum deprivation induces GSK-3beta activation in a pathway that leads to subsequent cell apoptosis. Intriguingly, this apoptotic cascade is amplified in presence of TLR4 but greatly attenuated by beta-arrestin 2, another critical molecule implicated in TLR4-mediated immune responses. Our data suggest that the association of beta-arrestin 2 with GSK-3beta contributes to the stabilization of phospho-GSK-3beta, an inactive form of GSK-3beta. It becomes a critical determinant for the attenuation of TLR4-initiated apoptosis by beta-arrestin 2. Taken together, we demonstrate that the TLR4 possesses the capability of accelerating GSK-3beta activation thereby deteriorating serum-deprivation-induced apoptosis; beta-arrestin 2 represents an inhibitory effect on the TLR4-mediated apoptotic cascade, through controlling the homeostasis of activation and inactivation of GSK-3beta.

Long-term efficacy and safety of human umbilical cord mesenchymal stromal cells in rotenone-induced hemiparkinsonian rats.

Several studies have shown functional improvements, neuroprotective, and neuroregenerative effects after mesenchymal stem cells transplantation to parkinsonian animal models. However, questions remain about the safety, feasibility, and long-term efficacy of this approach. In this study, we investigated migration, therapeutic, tumorigenesis, and epileptogenic effects of human umbilical cord mesenchymal stromal cells (HUMSCs) 1 year after transplantation into rotenone-induced hemiparkinsonian rats. Our data indicated that DiI-labeled HUMSCs migrated in the lesioned hemisphere, from corpus striatum (CPu) to substantia nigra. By integrating with host cells and differentiating into NSE, GFAP, Nestin, and tyrosine hydroxylase-positive cells, HUMSCs prevented 48.4% dopamine neurons from degeneration and 56.9% dopamine terminals from loss, both correlating with improvement of apomorphine-induced rotations. The CD50 and CD97 value of pentylenetetrazol and semiquantitative immunohistochemical analysis of proliferating cell nuclear antigen (PCNA), ß-catenin, C-myc, and NF-κB expression showed no significant difference between HUMSCs transplanted and untransplanted groups, whereas the expressions of Bcl-2 and P53 in the grafted CPu were upregulated by 281% and 200% compared to ungrafted CPu. The results of this long-term study suggest that HUMSCs transplantation, 1 of the most potential treatments for Parkinson's disease, is an effective and safe approach.

DNA polymerase-beta is required for 1-methyl-4-phenylpyridinium-induced apoptotic death in neurons.

The biochemical pathways that mediate the degeneration of dopaminergic neurons in the substantia nigra of patients with Parkinson's disease are largely unknown. Recently, aberrant cell cycle events have been shown to be associated with neuronal death in several neurodegenerative diseases. In the present study, we investigated the role of DNA polymerases (DNA pols) in 1-methyl-4-phenylpyridinium (MPP(+))-induced neuronal apoptosis in cerebellar granule cells. After exposure to MPP(+), the neurons entered S phase of the cell cycle. Neuronal cell cycle re-entry and apoptosis were attenuated by flavopiridol, which is a broad inhibitor of cyclin-dependent kinases (CDKs). MPP(+) exposure significantly increased the expression of DNA pol-beta and primase but did not affect the expression of the canonical replicative DNA pols, including DNA pol-delta and pol-epsilon. Dideoxycytidine, which is a pharmacological inhibitor of DNA pol-beta, attenuated the neuronal apoptosis mediated by MPP(+). In a similar manner, the expression of a dominant negative form of DNA pol-beta was also neuroprotective. These results suggest that DNA pol-beta may have a causal role in MPP(+)-induced neuronal apoptosis.

A meta-analysis of mood stabilizers for Alzheimer's disease.

The objective of this study was to assess the clinical evidence for or against mood stabilizers as a treatment for Alzheimer's disease (AD). We searched 5 databases from their inception to January 2010. Five randomized clinical trials of mood stabilizers to treat human patients suffering from AD were included. These trials assessed the effectiveness of mood stabilizers as an adjunct treatment to conventional anti-dementia drugs on behavioral and psychological symptoms, especially on agitation. Methodological quality was assessed using the Jadad score. The results suggested a significant effect in favor of placebo on the Mini-Mental Status Examination [n=270, weight mean difference (WMD), -0.89; 95% confidence intervals (CIs) -1.69 to -0.09, P=0.03] and on the Neuropsychiatric Inventory total (NPI total) (n=51, WMD, 3.71; 95% CIs 0.15 to 7.26, P=0.04). There were no significant differences in change scores on total Brief Psychiatric Rating Scale (BPRS total), NPI/BPRS agitation, Cohen-Mansfield Agitation Inventory total and Physical Self Maintenance Scale between mood stabilizers and placebo. Only one of these studies was free of methodological limitations (Jadad score=5). In conclusion, based on the existing evidence, mood stabilizers are ineffective or even harmful as a treatment for AD.

Developmental regulation of tau phosphorylation, tau kinases, and tau phosphatases.

Tau is a neuronal microtubule-associated protein. Its hyperphosphorylation plays a critical role in Alzheimer disease (AD). Expression and phosphorylation of tau are regulated developmentally, but its dynamic regulation and the responsible kinases or phosphatases remain elusive. Here, we studied the developmental regulation of tau in rats during development from embryonic day 15 through the age of 24 months. We found that tau expression increased sharply during the embryonic stage and then became relatively stable, whereas tau phosphorylation was much higher in developing brain than in mature brain. However, the extent of tau phosphorylation at seven of the 14 sites studied was much less in developing brain than in AD brain. Tau phosphorylation during development matched the period of active neurite outgrowth in general. Tau phosphorylation at various sites had different topographic distributions. Several tau kinases appeared to regulate tau phosphorylation collectively at overlapping sites, and the decrease of overall tau phosphorylation in adult brain might be due to the higher levels of tau phosphatases in mature brain. These studies provide new insight into the developmental regulation of site-specific tau phosphorylation and identify the likely sites required for the abnormal hyperphosphorylation of tau in AD.

Anesthesia induces phosphorylation of tau.

Abnormal hyperphosphorylation and aggregation of microtubule-associated protein tau play a crucial role in neurodegeneration of Alzheimer's disease (AD). Anesthesia has been associated with cognitive impairment and the risk for AD. Here we investigated the effects of anesthesia on site-specific tau phosphorylation and the possible mechanisms. We found that anesthesia for short periods (30 sec to 5 min) induced tau phosphorylation at Thr181, Ser199, Thr205, Thr212, Ser262, and Ser404 to small, but significant, extents, which appeared to result from anesthesia-induced activation of stress-activated protein kinases. Anesthesia for a longer time (1~h) induced much more dramatic phosphorylation of tau at the above sites, and the further phosphorylation may be associated with hypothermia induced by anesthesia. Anesthesia-induced tau phosphorylation appears to be specific because the increased phosphorylation was only seen at half of the tau phosphorylation sites studied and was not observed in global brain proteins. These studies clarified the dynamic changes of tau phosphorylation at various sites and, thus, served as a fundamental guide for future studies on tau phosphorylation by using brains of anesthetized experimental animals. Our findings also provide a possible mechanism by which anesthesia may cause postoperative cognitive impairment and increase the risk for AD.

Overexpression of Dyrk1A contributes to neurofibrillary degeneration in Down syndrome.

Adults with Down syndrome (DS) develop Alzheimer neurofibrillary degeneration in the brain, but the underlying molecular mechanism is unknown. Here, we report that the presence of an extra copy of the dual-specificity tyrosine-phosphorylated and regulated kinase 1A (Dyrk1A) gene due to trisomy 21 resulted in overexpression of Dyrk1A and elevated kinase activity in DS brain. Dyrk1A phosphorylated tau at several sites, and these sites were hyperphosphorylated in adult DS brains. Phosphorylation of tau by Dyrk1A primed its further phosphorylation by glycogen synthase kinase-3beta (GSK-3beta). Dyrk1A-induced tau phosphorylation inhibited tau's biological activity and promoted its self-aggregation. In Ts65Dn mouse brain, an extra copy of the Dyrk1A gene caused increased expression and activity of Dyrk1A and resulted in increased tau phosphorylation. These findings strongly suggest a novel mechanism by which the overexpression of Dyrk1A in DS brain causes neurofibrillary degeneration via hyperphosphorylating tau.

Sixteen-Week Interventional Study to Evaluate the Clinical Effects and Safety of Rivastigmine Capsules in Chinese Patients with Alzheimer's Disease.

BACKGROUND: Rivastigmine is a cholinesterase inhibitor, approved for the treatment of mild-to-moderate dementia of Alzheimer's type. OBJECTIVE: To explore the efficacy and safety of the maximal tolerated dose of rivastigmine capsules in Chinese patients with mild-to-moderate Alzheimer's disease (AD). METHODS: The study was a multicenter, open-label, single-arm, phase IV clinical study in mild-to-moderate drug-naïve AD patients treated with rivastigmine capsules. The primary endpoint was the changes in the total scores of Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) from baseline to week 16. Secondary endpoints included changes in the scores of the following assessment scales and safety: Alzheimer's Disease Cooperative Study; Activities of Daily Living; Mini-Mental Status Examination (MMSE); Neuropsychiatry Index (NPI), and Caregiver Burden Inventory. RESULTS: 222 patients were enrolled. Of these, 136 (75.1%) patients received and maintained the effective dose (≥6 mg/d) of rivastigmine for at least 4 weeks. The ADAS-Cog scale score improved in rivastigmine-treated patients at week 16 compared with baseline (p < 0.001) by 2.0 (95% CI: -3.0 to -1.1) points, which met the pre-defined superiority criteria. NPI-10 and NPI-12 scores improved by 3.6 and 4.0 points at week 16 (p = 0.001, p < 0.001), respectively. A total of 107 patients (59.1%) experienced adverse effects (AEs) during the study; common AEs included nausea (20.5%), vomiting (16.6%), anorexia (7.8%), dizziness (7.7%), and diarrhea (7.2%). CONCLUSION: This was the first phase IV study on rivastigmine in mainland China. The study preliminarily demonstrated that rivastigmine capsules showed good tolerability and efficacy in mild-to-moderate AD patients with the maximal tolerated dose.

Intranasal Insulin Prevents Anesthesia-induced Cognitive Impairments in Aged Mice.

BACKGROUND: Preclinical and clinical evidence suggests that elderly individuals are at increased risk of cognitive decline after general anesthesia. General anesthesia is also believed to be a risk factor for Postoperative Cognitive Dysfunction (POCD) and Alzheimer's Disease (AD). Intranasal administration of insulin, which delivers the drug directly into the brain, improves memory and cognition in both animal studies and small clinical trials. However, how insulin treatment improves cognitive function is poorly understood. METHODS: Aged mice were pretreated with intranasal insulin or saline before anesthesia. Propofol was added intraperitoneally to the mice from 7th day of insulin/saline treatment, and general anesthesia was induced and maintained for 2 hours/day for 5 consecutive days. Mice were evaluated at 26th day when the mice were continued on insulin or saline administration for another 15 days. RESULTS: We found that intranasal insulin treatment prevented anesthesia-induced cognitive impairments, as measured by novel object recognition test and contextual-dependent fear conditioning test. Insulin treatment also increased the expression level of Post-synaptic Density Protein 95 (PSD95), as well as upregulated Microtubule-associated Protein-2 (MAP-2) in the dentate gyrus of the hippocampus. Furthermore, we found that insulin treatment restored insulin signaling disturbed by anesthesia via activating PI3K/PDK1/AKT pathway, and attenuated anesthesia-induced hyperphosphorylation of tau at multiple AD-associated sites. We found the attenuation of tau hyperphosphorylation occurred by increasing the level of GSK3ß phosphorylated at Ser9, which leads to inactivation of GSK-3ß. CONCLUSION: Intranasal insulin administration might be a promising therapy to prevent anesthesiainduced cognitive deficit in elderly individuals.

MicroRNA-26a/Death-Associated Protein Kinase 1 Signaling Induces Synucleinopathy and Dopaminergic Neuron Degeneration in Parkinson's Disease.

BACKGROUND: Death-associated protein kinase 1 (DAPK1) is a widely distributed serine/threonine kinase that is critical for cell death in multiple neurological disorders, including Alzheimer's disease and stroke. However, little is known about the role of DAPK1 in the pathogenesis of Parkinson's disease (PD), the second most common neurodegenerative disorder. METHODS: We used Western blot and immunohistochemistry to evaluate the alteration of DAPK1. Quantitative polymerase chain reaction and fluorescence in situ hybridization were used to analyze the expression of microRNAs in PD mice and patients with PD. Rotarod, open field, and pole tests were used to evaluate the locomotor ability. Immunofluorescence, Western blot, and filter traps were used to evaluate synucleinopathy in PD mice. RESULTS: We found that DAPK1 is posttranscriptionally upregulated by a reduction in microRNA-26a (miR-26a) caused by a loss of the transcription factor CCAAT enhancer-binding protein alpha. The overexpression of DAPK1 in PD mice is positively correlated with neuronal synucleinopathy. Suppressing miR-26a or upregulating DAPK1 results in synucleinopathy, dopaminergic neuron cell death, and motor disabilities in wild-type mice. In contrast, genetic deletion of DAPK1 in dopaminergic neurons by crossing DAT-Cre mice with DAPK1 floxed mice effectively rescues the abnormalities in mice with chronic MPTP treatment. We further showed that DAPK1 overexpression promotes PD-like phenotypes by direct phosphorylation of α-synuclein at the serine 129 site. Correspondingly, a cell-permeable competing peptide that blocks the phosphorylation of α-synuclein prevents motor disorders, synucleinopathy, and dopaminergic neuron loss in the MPTP mice. CONCLUSIONS: miR-26a/DAPK1 signaling cascades are essential in the formation of the molecular and cellular pathologies in PD.

Decrease of protein phosphatase 2A and its association with accumulation and hyperphosphorylation of tau in Down syndrome.

Virtually all individuals with Down syndrome (DS) develop neurofibrillary tangles, a characteristic brain lesion of Alzheimer's disease (AD), when they reach the fourth decade of life. In AD, neurofibrillary tangles are thought to result from abnormal hyperphosphorylation of tau protein, which, in turn, can result from down-regulation of protein phosphatase (PP) 2A, a major brain tau phosphatase. The abnormal hyperphosphorylation of tau in DS had not yet been characterized, and its causes were not understood. In this study, by using quantitative Western blot analysis, we found that the level of the catalytic subunit of PP2A, but not of PP1, PP2B or PP5, was dramatically decreased. The decrease of PP2A level correlated negatively to tau level and tau phosphorylation at several abnormal hyperphosphorylation sites, including Ser199, Thr205, Thr212, Ser262, Ser396 and Ser422. Our results indicate that PP2A is down-regulated in DS brain and suggest that this down-regulation might be involved in the abnormal hyperphosphorylation and accumulation of tau.

Correction: A Chinese version of the Language Screening Test (CLAST) for early-stage stroke patients.

[This corrects the article DOI: 10.1371/journal.pone.0196646.].