Impact of the South Atlantic Anomaly on radiation exposure at flight altitudes during solar minimum.

The South Atlantic Anomaly (SAA) is a geographical region over the South Atlantic Ocean where the inner Van Allen radiation belt extends down particularly close to Earth. This leads to highly increased levels of ionizing radiation and related impacts on spacecraft in Low Earth Orbits, e.g., correspondingly increased radiation exposure of astronauts and electronic components on the International Space Station. According to an urban legend, the SAA is also supposed to affect the radiation field in the atmosphere even down to the altitudes of civil aviation. In order to identify and quantify any additional contributions to the omnipresent radiation exposure due to the Galactic Cosmic Radiation at flight altitudes, comprehensive measurements were performed crossing the geographical region of the SAA at an altitude of 13 km in a unique flight mission-Atlantic Kiss. No indication of increased radiation exposure was found.

CERAD-NAB and flexible battery based neuropsychological differentiation of Alzheimer's dementia and depression using machine learning approaches.

Depression (DEP) and dementia of the Alzheimer's type (DAT) represent the most common neuropsychiatric disorders in elderly patients. Accurate differential diagnosis is indispensable to ensure appropriate treatment. However, DEP can yet mimic cognitive symptoms of DAT and patients with DAT often also present with depressive symptoms, impeding correct diagnosis. Machine learning (ML) approaches could eventually improve this discrimination using neuropsychological test data, but evidence is still missing. We therefore employed Support Vector Machine (SVM), Naïve Bayes (NB), Random Forest (RF) and conventional Logistic Regression (LR) to retrospectively predict the diagnoses of 189 elderly patients (68 DEP and 121 DAT) based on either the well-established Consortium to Establish a Registry for Alzheimer's Disease neuropsychological assessment battery (CERAD-NAB) or a flexible battery approach (FLEXBAT). The best performing combination consisted of FLEXBAT and NB, correctly classifying 87.0% of patients as either DAT or DEP. However, all accuracies were similar across algorithms and test batteries (83.0% - 87.0%). Accordingly, our study is the first to show that common ML algorithms with their default parameters can accurately differentiate between patients clinically diagnosed with DAT or DEP using neuropsychological test data, but do not necessarily outperform conventional LR.

Uncovering specificity of endogenous TAU aggregation in a human iPSC-neuron TAU seeding model.

Tau pathobiology has emerged as a key component underlying Alzheimer's disease (AD) progression; however, human neuronal in vitro models have struggled to recapitulate tau phenomena observed in vivo. Here, we aimed to define the minimal requirements to achieve endogenous tau aggregation in functional neurons utilizing human induced pluripotent stem cell (hiPSC) technology. Optimized hiPSC-derived cortical neurons seeded with AD brain-derived competent tau species or recombinant tau fibrils displayed increases in insoluble, endogenous tau aggregates. Importantly, MAPT-wild type and MAPT-mutant hiPSC-neurons exhibited unique propensities for aggregation dependent on the seed strain rather than the repeat domain identity, suggesting that successful templating of the recipient tau may be driven by the unique conformation of the seed. The in vitro model presented here represents the first successful demonstration of combining human neurons, endogenous tau expression, and AD brain-derived competent tau species, offering a more physiologically relevant platform to study tau pathobiology.

Identification of cis-acting determinants mediating the unconventional secretion of tau.

The deposition of tau aggregates throughout the brain is a pathological characteristic within a group of neurodegenerative diseases collectively termed tauopathies, which includes Alzheimer's disease. While recent findings suggest the involvement of unconventional secretory pathways driving tau into the extracellular space and mediating the propagation of the disease-associated pathology, many of the mechanistic details governing this process remain elusive. In the current study, we provide an in-depth characterization of the unconventional secretory pathway of tau and identify novel molecular determinants that are required for this process. Here, using Drosophila models of tauopathy, we correlate the hyperphosphorylation and aggregation state of tau with the disease-related neurotoxicity. These newly established systems recapitulate all the previously identified hallmarks of tau secretion, including the contribution of tau hyperphosphorylation as well as the requirement for PI(4,5)P2 triggering the direct translocation of tau. Using a series of cellular assays, we demonstrate that both the sulfated proteoglycans on the cell surface and the correct orientation of the protein at the inner plasma membrane leaflet are critical determinants of this process. Finally, we identify two cysteine residues within the microtubule binding repeat domain as novel cis-elements that are important for both unconventional secretion and trans-cellular propagation of tau.

Autophagy inhibition rescues structural and functional defects caused by the loss of mitochondrial chaperone Hsc70-5 in Drosophila.

We investigated in larval and adult Drosophila models whether loss of the mitochondrial chaperone Hsc70-5 is sufficient to cause pathological alterations commonly observed in Parkinson disease. At affected larval neuromuscular junctions, no effects on terminal size, bouton size or number, synapse size, or number were observed, suggesting that we studied an early stage of pathogenesis. At this stage, we noted a loss of synaptic vesicle proteins and active zone components, delayed synapse maturation, reduced evoked and spontaneous excitatory junctional potentials, increased synaptic fatigue, and cytoskeleton rearrangements. The adult model displayed ATP depletion, altered body posture, and susceptibility to heat-induced paralysis. Adult phenotypes could be suppressed by knockdown of dj-1ß, Lrrk, DCTN2-p50, DCTN1-p150, Atg1, Atg101, Atg5, Atg7, and Atg12. The knockdown of components of the macroautophagy/autophagy machinery or overexpression of human HSPA9 broadly rescued larval and adult phenotypes, while disease-associated HSPA9 variants did not. Overexpression of Pink1 or promotion of autophagy exacerbated defects.Abbreviations: AEL: after egg laying; AZ: active zone; brp: bruchpilot; Csp: cysteine string protein; dlg: discs large; eEJPs: evoked excitatory junctional potentials; GluR: glutamate receptor; H2O2: hydrogen peroxide; mEJP: miniature excitatory junctional potentials; MT: microtubule; NMJ: neuromuscular junction; PD: Parkinson disease; Pink1: PTEN-induced putative kinase 1; PSD: postsynaptic density; SSR: subsynaptic reticulum; SV: synaptic vesicle; VGlut: vesicular glutamate transporter.

Regional Cerebral Associations Between Psychometric Tests and Imaging Biomarkers in Alzheimer's Disease.

Recently, imaging biomarkers have gained importance for the characterization of patients with Alzheimer's disease; however, the relationship between regional biomarker expression and cognitive function remains unclear. In our study, we investigated associations between scores on CERAD neuropsychological assessment battery (CERAD-NAB) subtests with regional glucose metabolism, cortical thickness and amyloid deposition in patients with early Alzheimer's disease (AD) using [18F]-fluorodeoxyglucose (FDG), structural MRI, and 11C-Pittsburgh Compound B (PiB) positron emission tomography (PET), respectively. A total of 76 patients (mean age 68.4 ± 8.5 years, 57.9% male) with early AD (median global clinical dementia rating (CDR) score = 0.5, range: 0.5-2.0) were studied. Associations were investigated by correlation and multiple regression analyses. Scores on cognitive subtests were most closely predicted by regional glucose metabolism with explained variance up to a corrected R² of 0.518, followed by cortical thickness and amyloid deposition. Prediction of cognitive subtest performance was increased up to a corrected R² of 0.622 for Word List-Delayed Recall, when biomarker information from multiple regions and multiple modalities were included. For verbal, visuoconstructive and mnestic domains the closest associations with FDG-PET imaging were found in the left lateral temporal lobe, right parietal lobe, and posterior cingulate cortex, respectively. Decreased cortical thickness in parietal regions was most predictive of impaired subtest performance. Remarkably, cerebral amyloid deposition significantly predicted cognitive function in about half of the subtests but with smaller extent of variance explained (corrected R² ≤ 0.220). We conclude that brain metabolism and atrophy affect cognitive performance in a regionally distinct way. Significant predictions of cognitive function by PiB-PET in half of CERAD-NAB subtests suggest functional relevance even in symptomatic patients with AD, challenging the concept of plateauing cortical amyloid deposition early in the disease course. Our results underscore the complex spatial relationship between different imaging biomarkers.

Disassembly of Tau fibrils by the human Hsp70 disaggregation machinery generates small seeding-competent species.

The accumulation of amyloid Tau aggregates is implicated in Alzheimer's disease (AD) and other tauopathies. Molecular chaperones are known to maintain protein homeostasis. Here, we show that an ATP-dependent human chaperone system disassembles Tau fibrils in vitro We found that this function is mediated by the core chaperone HSC70, assisted by specific cochaperones, in particular class B J-domain proteins and a heat shock protein 110 (Hsp110)-type nucleotide exchange factor (NEF). The Hsp70 disaggregation machinery processed recombinant fibrils assembled from all six Tau isoforms as well as Sarkosyl-resistant Tau aggregates extracted from cell cultures and human AD brain tissues, demonstrating the ability of the Hsp70 machinery to recognize a broad range of Tau aggregates. However, the chaperone activity released monomeric and small oligomeric Tau species, which induced the aggregation of self-propagating Tau conformers in a Tau cell culture model. We conclude that the activity of the Hsp70 disaggregation machinery is a double-edged sword, as it eliminates Tau amyloids at the cost of generating new seeds.

N368-Tau fragments generated by legumain are detected only in trace amount in the insoluble Tau aggregates isolated from AD brain.

Intraneuronal insoluble inclusions made of Tau protein are neuropathological hallmarks of Alzheimer Disease (AD). Cleavage of Tau by legumain (LGMN) has been proposed to be crucial for aggregation of Tau into fibrils. However, it remains unclear if LGMN-cleaved Tau fragments accumulate in AD Tau inclusions.Using an in vitro enzymatic assay and non-targeted mass spectrometry, we identified four putative LGMN cleavage sites at Tau residues N167-, N255-, N296- and N368. Cleavage at N368 generates variously sized N368-Tau fragments that are aggregation prone in the Thioflavin T assay in vitro. N368-cleaved Tau is not detected in the brain of legumain knockout mice, indicating that LGMN is required for Tau cleavage in the mouse brain in vivo. Using a targeted mass spectrometry method in combination with tissue fractionation and biochemical analysis, we investigated whether N368-cleaved Tau is differentially produced and aggregated in brain of AD patients and control subjects. In brain soluble extracts, despite reduced uncleaved Tau in AD, levels of N368-cleaved Tau are comparable in AD and control hippocampus, suggesting that LGMN-mediated cleavage of Tau is not altered in AD. Consistently, levels of activated, cleaved LGMN are also similar in AD and control brain extracts. To assess the potential accumulation of N368-cleaved Tau in insoluble Tau aggregates, we analyzed sarkosyl-insoluble extracts from AD and control hippocampus. Both N368-cleaved Tau and uncleaved Tau were significantly increased in AD as a consequence of pathological Tau inclusions accumulation. However, the amount of N368-cleaved Tau represented only a very minor component (< 0.1%) of insoluble Tau.Our data indicate that LGMN physiologically cleaves Tau in the mouse and human brain generating N368-cleaved Tau fragments, which remain largely soluble and are present only in low proportion in Tau insoluble aggregates compared to uncleaved Tau. This suggests that LGMN-cleaved Tau has limited role in the progressive accumulation of Tau inclusions in AD.

Applying Psycholinguistic Evidence to the Construction of a New Test of Verbal Memory in Late-Life Cognitive Decline: The Auditory Wordlist Learning Test.

The construction of the German Auditory Wordlist Learning Test (AWLT) for the assessment of verbal memory in late-life cognitive decline was guided by psycholinguistic evidence, which indicates that a word's linguistic characteristics influence its probability of being learned and recalled. The AWLT includes four trials of learning, short and long delayed free recall, and a recognition task. Its words were selected with taking into account their semantic content, orthographic length, frequency in the language, and orthographic neighborhood size (the number of words derived by adding, subtracting, or replacing a single letter at a time). Through this method, it was possible to better control item and test difficulty, improve the similarity between parallel forms, and reduce bias through recall advantages for certain words due to their linguistic characteristics. In two pilot studies with cognitively healthy subjects, the AWLT showed good internal consistency, split-half reliability, and parallel forms reliability and proved able to assess learning, retention, and recognition. Overall, linguistic recall effects were mitigated; however, an advantage for high-frequency words was observed.

Changes in Glutathione Redox Potential Are Linked to Aß42-Induced Neurotoxicity.

Glutathione is the major low-molecular weight thiol of eukaryotic cells. It is central to one of the two major NADPH-dependent reducing systems and is likely to play a role in combating oxidative stress, a process suggested to play a key role in Alzheimer's disease (AD). However, the nature and relevance of redox changes in the onset and progression of AD are still uncertain. Here, we combine genetically encoded redox sensors with our Drosophila models of amyloid-beta (Aß) aggregation. We find that changes in glutathione redox potential (EGSH) closely correlate with disease onset and progression. We observe this redox imbalance specifically in neurons, but not in glia cells. EGSH changes and Aß42 deposition are also accompanied by increased JNK stress signaling. Furthermore, pharmacologic and genetic manipulation of glutathione synthesis modulates Aß42-mediated neurotoxicity, suggesting a causal relationship between disturbed glutathione redox homeostasis and early AD pathology.

The Montreal Cognitive Assessment: Normative Data from a German-Speaking Cohort and Comparison with International Normative Samples.

BACKGROUND: The Montreal Cognitive Assessment (MoCA) is used to evaluate multiple cognitive domains in elderly individuals. However, it is influenced by demographic characteristics that have yet to be adequately considered. OBJECTIVE: The aim of our study was to investigate the effects of age, education, and sex on the MoCA total score and to provide demographically adjusted normative values for a German-speaking population. METHODS: Subjects were recruited from a registry of healthy volunteers. Cognitive health was defined using the Mini-Mental State Examination (score ≥27/30 points) and the Consortium to Establish a Registry for Alzheimer's Disease-Neuropsychological Assessment Battery (total score ≥85.9 points). Participants were assessed with the German version of the MoCA. Normative values were developed based on regression analysis. Covariates were chosen using the Predicted Residual Sums of Squares approach. RESULTS: The final sample consisted of 283 participants (155 women, 128 men; mean (SD) age = 73.8 (5.2) years; education = 13.6 (2.9) years). Thirty-one percent of participants scored below the original cut-off (<26/30 points). The MoCA total score was best predicted by a regression model with age, education, and sex as covariates. Older age, lower education, and male sex were associated with a lower MoCA total score (p < 0.001). CONCLUSION: We developed a formula to provide demographically adjusted standard scores for the MoCA in a German-speaking population. A comparison with other MoCA normative studies revealed considerable differences with respect to selection of volunteers and methods used to establish normative data.

Unconventional Secretion Mediates the Trans-cellular Spreading of Tau.

The progressive deposition of misfolded hyperphosphorylated tau is a pathological hallmark of tauopathies, including Alzheimer's disease. However, the underlying molecular mechanisms governing the intercellular spreading of tau species remain elusive. Here, we show that full-length soluble tau is unconventionally secreted by direct translocation across the plasma membrane. Increased secretion is favored by tau hyperphosphorylation, which provokes microtubule detachment and increases the availability of free protein inside cells. Using a series of binding assays, we show that free tau interacts with components enriched at the inner leaflet of the plasma membrane, finally leading to its translocation across the plasma membrane mediated by sulfated proteoglycans. We provide further evidence that secreted soluble tau species spread trans-cellularly and are sufficient for the induction of intracellular tau aggregation in adjacent cells. Our study demonstrates the mechanistic details of tau secretion and provides insights into the initiation and progression of tau pathology.

Seed-induced acceleration of amyloid-ß mediated neurotoxicity in vivo.

Seeded propagation of amyloid-beta (Aß) pathology is suggested to contribute to the progression of Alzheimer's disease. Local overproduction of aggregation-prone Aß variants could explain the focal initiation of a seeding cascade that subsequently triggers widespread pathology. Several animal models support this seeding concept by demonstrating accelerated Aß deposition following inoculation with Aß-containing homogenates, however its role in progressive neurodegeneration remains unclear. Here, we present a non-invasive approach to study Aß seeding processes in vivo using Drosophila models. We show that small amounts of aggregation-competent Aß42 seeds, generated in selected neuronal clusters, can induce the deposition of the pan-neuronally expressed and otherwise soluble Aß40. Moreover, our models visualize the accelerated formation and propagation of amyloid pathology throughout the brain, which correlates with severe neurotoxicity. Taken together, these in vivo models provide mechanistic insights into disease-related processes and represent versatile genetic tools to determine novel modifiers of the Aß seeding cascade.Seeding of amyloid beta from one brain region to another is thought to contribute to the progression of Alzheimer's disease, although to date most studies have depended on inoculation of animals with exogenous amyloid. Here the authors describe a genetic seed and target system in Drosophila which may be useful for the mechanistic study of seeding of amyloid in vivo.

Bin1 directly remodels actin dynamics through its BAR domain.

Endocytic processes are facilitated by both curvature-generating BAR-domain proteins and the coordinated polymerization of actin filaments. Under physiological conditions, the N-BAR protein Bin1 has been shown to sense and curve membranes in a variety of cellular processes. Recent studies have identified Bin1 as a risk factor for Alzheimer's disease, although its possible pathological function in neurodegeneration is currently unknown. Here, we report that Bin1 not only shapes membranes, but is also directly involved in actin binding through its BAR domain. We observed a moderate actin bundling activity by human Bin1 and describe its ability to stabilize actin filaments against depolymerization. Moreover, Bin1 is also involved in stabilizing tau-induced actin bundles, which are neuropathological hallmarks of Alzheimer's disease. We also provide evidence for this effect in vivo, where we observed that downregulation of Bin1 in a Drosophila model of tauopathy significantly reduces the appearance of tau-induced actin inclusions. Together, these findings reveal the ability of Bin1 to modify actin dynamics and provide a possible mechanistic connection between Bin1 and tau-induced pathobiological changes of the actin cytoskeleton.

Restraint of presynaptic protein levels by Wnd/DLK signaling mediates synaptic defects associated with the kinesin-3 motor Unc-104.

The kinesin-3 family member Unc-104/KIF1A is required for axonal transport of many presynaptic components to synapses, and mutation of this gene results in synaptic dysfunction in mice, flies and worms. Our studies at the Drosophila neuromuscular junction indicate that many synaptic defects in unc-104-null mutants are mediated independently of Unc-104's transport function, via the Wallenda (Wnd)/DLK MAP kinase axonal damage signaling pathway. Wnd signaling becomes activated when Unc-104's function is disrupted, and leads to impairment of synaptic structure and function by restraining the expression level of active zone (AZ) and synaptic vesicle (SV) components. This action concomitantly suppresses the buildup of synaptic proteins in neuronal cell bodies, hence may play an adaptive role to stresses that impair axonal transport. Wnd signaling also becomes activated when pre-synaptic proteins are over-expressed, suggesting the existence of a feedback circuit to match synaptic protein levels to the transport capacity of the axon.

The KIF1A homolog Unc-104 is important for spontaneous release, postsynaptic density maturation and perisynaptic scaffold organization.

The kinesin-3 family member KIF1A has been shown to be important for experience dependent neuroplasticity. In Drosophila, amorphic mutations in the KIF1A homolog unc-104 disrupt the formation of mature boutons. Disease associated KIF1A mutations have been associated with motor and sensory dysfunctions as well as non-syndromic intellectual disability in humans. A hypomorphic mutation in the forkhead-associated domain of Unc-104, unc-104bris, impairs active zone maturation resulting in an increased fraction of post-synaptic glutamate receptor fields that lack the active zone scaffolding protein Bruchpilot. Here, we show that the unc-104brismutation causes defects in synaptic transmission as manifested by reduced amplitude of both evoked and miniature excitatory junctional potentials. Structural defects observed in the postsynaptic compartment of mutant NMJs include reduced glutamate receptor field size, and altered glutamate receptor composition. In addition, we observed marked loss of postsynaptic scaffolding proteins and reduced complexity of the sub-synaptic reticulum, which could be rescued by pre- but not postsynaptic expression of unc-104. Our results highlight the importance of kinesin-3 based axonal transport in synaptic transmission and provide novel insights into the role of Unc-104 in synapse maturation.

The Drosophila KIF1A Homolog unc-104 Is Important for Site-Specific Synapse Maturation.

Mutations in the kinesin-3 family member KIF1A have been associated with hereditary spastic paraplegia (HSP), hereditary and sensory autonomic neuropathy type 2 (HSAN2) and non-syndromic intellectual disability (ID). Both autosomal recessive and autosomal dominant forms of inheritance have been reported. Loss of KIF1A or its homolog unc-104 causes early postnatal or embryonic lethality in mice and Drosophila, respectively. In this study, we use a previously described hypomorphic allele of unc-104, unc-104(bris) , to investigate the impact of partial loss-of-function of kinesin-3 on synapse maturation at the Drosophila neuromuscular junction (NMJ). Unc-104(bris) mutants exhibit structural defects where a subset of synapses at the NMJ lack all investigated active zone (AZ) proteins, suggesting a complete failure in the formation of the cytomatrix at the active zone (CAZ) at these sites. Modulating synaptic Bruchpilot (Brp) levels by ectopic overexpression or RNAi-mediated knockdown suggests that the loss of AZ components such as Ca(2+) channels and Liprin-α is caused by impaired kinesin-3 based transport rather than due to the absence of the key AZ organizer protein, Brp. In addition to defects in CAZ assembly, unc-104(bris) mutants display further defects such as depletion of dense core and synaptic vesicle (SV) markers from the NMJ. Notably, the level of Rab3, which is important for the allocation of AZ proteins to individual release sites, was severely reduced at unc-104(bris) mutant NMJs. Overexpression of Rab3 partially ameliorates synaptic phenotypes of unc-104(bris) larvae, suggesting that lack of presynaptic Rab3 contributes to defects in synapse maturation.

Differential Linguistic Recall Effects in the California Verbal Learning Test in Healthy Aging and Alzheimer's Dementia: Analysis of Routine Diagnostic Data.

OBJECTIVE: Psycholinguistic evidence suggests that certain word characteristics might influence recall rates in word-list learning tests. These effects were investigated in the German California Verbal Learning Test (CVLT-G) in a clinical setting. METHOD: Subjects were memory clinic patients without cognitive diagnosis (N = 45) and with dementia of the Alzheimer type (DAT) (N = 48) matched for age, sex, depressive symptoms, and education. The CVLT-G's words were analyzed with regard to length, frequency, and neighborhood size and dichotomized into low and high value groups. For each linguistic variable, a 2 (diagnosis: control vs. DAT) × 3 (time: Trial 1 vs. Trial 5 vs. Long Delay Free Recall) × 2 (linguistic: low vs. high) repeated measures analysis of variance (RM-ANOVA) was conducted. RESULTS: RM-ANOVAs revealed a main effect for frequency, F(1,91) = 21.03, p < 0.001, and interactions between time and frequency, F(1.97,179.09) = 5.18, p = 0.007, and diagnosis and neighborhood, F(1.77,161.23) = 13.60, p < 0.001. High-frequency words were better recalled at Trial 5 (Cohen's d = 0.37) and long delayed free recall (d = 0.16) and learning from Trials 1 to 5 was better for high-frequency words (d = 0.39). Controls recalled large neighborhood words better whereas the opposite was true for persons with DAT (d = 0.76). CONCLUSION: Frequency and neighborhood size seem to influence learning and retention in the CVLT-G with neighborhood size producing opposed effects for persons with and without DAT. These results are in line with international experimental studies and likely not specific to the German language. Potential diagnostic implications and possibilities for test construction and interpretation are discussed.

Psychoeducation Improves Compliance and Outcome in Schizophrenia Without an Increase of Adverse Side Effects: A 7-Year Follow-up of the Munich PIP-Study.

Psychoeducation improves adherence and motivates patients to accept a maintenance therapy as recommended by the guidelines. This would mean a daily consumption of at least 300 chlorpromazine (CPZ) units in the long run and should lead to an increase of the antipsychotic dosage in comparison to patients with treatment as usual (TAU). This raises 2 important questions: whether more side effects are provoked and do the patients have a corresponding benefit with a better outcome. A total of 41 patients with a diagnosis of schizophrenic or schizoaffective disorder were randomized at study entry, either to bifocal psychoeducation (21), or to standard treatment (20). They were compared concerning compliance, type of medication, dosage (CPZ equivalents), motor side effects and number of days in hospital. The average daily antipsychotic medication 2 and 7 years after index discharge was 365 and 354 CPZ-units respectively in the intervention group (IG), but 247 and 279, respectively in the control group (CG). The extent of motor side effects was slightly smaller in the IG, but they showed a small and statistically not significant increase in the rate of tardive dyskinesia (TD) after 7 years. At the 7-year follow-up the patients in the IG had spent 74.7 days in hospital compared to 243.4 days for the patients in the CG (P < .05). The course of illness was significantly better in the IG without increasing motor side-effects. Therefore, psychoeducation should be integrated more systematically into the routine treatment. These data are part of a previous study, published 2007, with a sample size of 48 patients. Seven patients-3 of the IG and 4 of the CG-could not be included, because they were not able to complete the very complex "Computer-based kinematic analysis of motor performance." In this article all conclusions are referred to the new sample size, therefore some results are slightly different in comparison to the previous data.

Cellular and molecular modifier pathways in tauopathies: the big picture from screening invertebrate models.

Abnormal tau accumulations were observed and documented in post-mortem brains of patients affected by Alzheimer's disease (AD) long before the identification of mutations in the Microtubule-associated protein tau (MAPT) gene, encoding the tau protein, in a different neurodegenerative disease called Frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). The discovery of mutations in the MAPT gene associated with FTDP-17 highlighted that dysfunctions in tau alone are sufficient to cause neurodegeneration. Invertebrate models have been diligently utilized in investigating tauopathies, contributing to the understanding of cellular and molecular pathways involved in disease etiology. An important discovery came with the demonstration that over-expression of human tau in Drosophila leads to premature mortality and neuronal dysfunction including neurodegeneration, recapitulating some key neuropathological features of the human disease. The simplicity of handling invertebrate models combined with the availability of a diverse range of experimental resources make these models, in particular Drosophila a powerful invertebrate screening tool. Consequently, several large-scale screens have been performed using Drosophila, to identify modifiers of tau toxicity. The screens have revealed not only common cellular and molecular pathways, but in some instances the same modifier has been independently identified in two or more screens suggesting a possible role for these modifiers in regulating tau toxicity. The purpose of this review is to discuss the genetic modifier screens on tauopathies performed in Drosophila and C. elegans models, and to highlight the common cellular and molecular pathways that have emerged from these studies. Here, we summarize results of tau toxicity screens providing mechanistic insights into pathological alterations in tauopathies. Key pathways or modifiers that have been identified are associated with a broad range of processes including, but not limited to, phosphorylation, cytoskeleton organization, axonal transport, regulation of cellular proteostasis, transcription, RNA metabolism, cell cycle regulation, and apoptosis. We discuss the utility and application of invertebrate models in elucidating the cellular and molecular functions of novel and uncharacterized disease modifiers identified in large-scale screens as well as for investigating the function of genes identified as risk factors in genome-wide association studies from human patients in the post-genomic era. In this review, we combined and summarized several large-scale modifier screens performed in invertebrate models to identify modifiers of tau toxicity. A summary of the screens show that diverse cellular processes are implicated in the modification of tau toxicity. Kinases and phosphatases are the most predominant class of modifiers followed by components required for cellular proteostasis and axonal transport and cytoskeleton elements.