Autophagy induction halts axonal degeneration in a mouse model of X-adrenoleukodystrophy
Abstract X-linked adrenoleukodystrophy (X-ALD) is a rare neurometabolic disease characterized by the accumulation of very long chain fatty acids (VLCFAs) due to a loss of function of the peroxisomal transporter ABCD1. Here, using in vivo and in vitro models, we demonstrate that autophagic flux was impaired due to elevated mammalian target of rapamycin (mTOR) signaling, which contributed to X-ALD pathogenesis. We also show that excess VLCFAs downregulated autophagy in human fibroblasts. Furthermore, mTOR inhibition by a rapamycin derivative (temsirolimus) restored autophagic flux and inhibited the axonal degenerati...
Source: Acta Neuropathologica - December 31, 2014 Category: Neurology Source Type: research

Frontotemporal lobar degeneration: defining phenotypic diversity through personalized medicine
Abstract Frontotemporal lobar degeneration (FTLD) comprises two main classes of neurodegenerative diseases characterized by neuronal/glial proteinaceous inclusions (i.e., proteinopathies) including tauopathies (i.e., FTLD-Tau) and TDP-43 proteinopathies (i.e., FTLD-TDP) while other very rare forms of FTLD are known such as FTLD with FUS pathology (FTLD-FUS). This review focuses mainly on FTLD-Tau and FLTD-TDP, which may present as several clinical syndromes: a behavioral/dysexecutive syndrome (behavioral variant frontotemporal dementia); language disorders (primary progressive aphasia variants); and motor disorder...
Source: Acta Neuropathologica - December 31, 2014 Category: Neurology Source Type: research

Neutrophil recruitment to the brain in mouse and human ischemic stroke
Abstract Neutrophils are rapidly recruited in response to local tissue infection or inflammation. Stroke triggers a strong inflammatory reaction but the relevance of neutrophils in the ischemic brain is not fully understood, particularly in the absence of reperfusion. We investigated brain neutrophil recruitment in two murine models of permanent ischemia induced by either cauterization of the distal portion of the middle cerebral artery (c-MCAo) or intraluminal MCA occlusion (il-MCAo), and three fatal cases of human ischemic stroke. Flow cytometry analyses revealed progressive neutrophil recruitment after c-MCAo, ...
Source: Acta Neuropathologica - December 30, 2014 Category: Neurology Source Type: research

One is the deadliest number: the detrimental effects of social isolation on cerebrovascular diseases and cognition
Abstract The deleterious effects of chronic social isolation (SI) have been recognized for several decades. Isolation is a major source of psychosocial stress and is associated with an increased prevalence of vascular and neurological diseases. In addition, isolation exacerbates morbidity and mortality following acute injuries such as stroke or myocardial infarction. In contrast, affiliative social interactions can improve organismal function and health. The molecular mechanisms underlying these effects are unknown. Recently, results from large epidemiological trials and pre-clinical studies have revealed several ...
Source: Acta Neuropathologica - December 23, 2014 Category: Neurology Source Type: research

Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer’s disease or corticobasal degeneration brains
Abstract Filamentous tau pathologies are hallmark lesions of several neurodegenerative tauopathies including Alzheimer’s disease (AD) and corticobasal degeneration (CBD) which show cell type-specific and topographically distinct tau inclusions. Growing evidence supports templated transmission of tauopathies through functionally interconnected neuroanatomical pathways suggesting that different self-propagating strains of pathological tau could account for the diverse manifestations of neurodegenerative tauopathies. Here, we describe the rapid and distinct cell type-specific spread of pathological tau followin...
Source: Acta Neuropathologica - December 23, 2014 Category: Neurology Source Type: research

Neuropathology and biochemistry of Aβ and its aggregates in Alzheimer’s disease
Abstract Alzheimer’s disease (AD) is characterized by β-amyloid plaques and intraneuronal τ aggregation usually associated with cerebral amyloid angiopathy (CAA). Both β-amyloid plaques and CAA deposits contain fibrillar aggregates of the amyloid β-peptide (Aβ). Aβ plaques and CAA develop first in neocortical areas of preclinical AD patients and, then, expand in a characteristic sequence into further brain regions with end-stage pathology in symptomatic AD patients. Aβ aggregates are not restricted to amyloid plaques and CAA. Soluble and several types of insoluble non-plaque...
Source: Acta Neuropathologica - December 23, 2014 Category: Neurology Source Type: research

Traumatic brain injury-induced axonal phenotypes react differently to treatment
Abstract Injured axons with distinct morphologies have been found following mild traumatic brain injury (mTBI), although it is currently unclear whether they reflect varied responses to the injury or represent different stages of progressing pathology. This complicates evaluation of therapeutic interventions targeting axonal injury. To address this issue, we assessed axonal injury over time within a well-defined axonal population, while also evaluating mitochondrial permeability transition as a therapeutic target. We utilized mice expressing yellow fluorescent protein (YFP) in cortical neurons which were crossed w...
Source: Acta Neuropathologica - December 21, 2014 Category: Neurology Source Type: research

Erratum to: Acute function of secreted amyloid precursor protein fragment APPsα in synaptic plasticity
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - December 19, 2014 Category: Neurology Source Type: research

Perivascular microglia promote blood vessel disintegration in the ischemic penumbra
Abstract The contribution of microglia to ischemic cortical stroke is of particular therapeutic interest because of the impact on the survival of brain tissue in the ischemic penumbra, a region that is potentially salvable upon a brain infarct. Whether or not tissue in the penumbra survives critically depends on blood flow and vessel perfusion. To study the role of microglia in cortical stroke and blood vessel stability, CX3CR1+/GFP mice were subjected to transient middle cerebral artery occlusion and then microglia were investigated using time-lapse two-photon microscopy in vivo. Soon after reperfusion, microglia...
Source: Acta Neuropathologica - December 12, 2014 Category: Neurology Source Type: research

Tau aggregation and its interplay with amyloid-β
Abstract Neurofibrillary tangles and amyloid plaques constitute the hallmark brain lesions of Alzheimer’s disease (AD) patients. Tangles are composed of fibrillar aggregates of the microtubule-associated protein tau, and plaques comprise fibrillar forms of a proteolytic cleavage product, amyloid-β (Aβ). Although plaques and tangles are the end-stage lesions in AD, small oligomers of Aβ and tau are now receiving increased attention as they are shown to correlate best with neurotoxicity. One key question of debate, however, is which of these pathologies appears first and hence is upstream in the...
Source: Acta Neuropathologica - December 9, 2014 Category: Neurology Source Type: research

Acute function of secreted amyloid precursor protein fragment APPsα in synaptic plasticity
Abstract The key role of APP in the pathogenesis of Alzheimer disease is well established. However, postnatal lethality of double knockout mice has so far precluded the analysis of the physiological functions of APP and the APLPs in the brain. Previously, APP family proteins have been implicated in synaptic adhesion, and analysis of the neuromuscular junction of constitutive APP/APLP2 mutant mice showed deficits in synaptic morphology and neuromuscular transmission. Here, we generated animals with a conditional APP/APLP2 double knockout (cDKO) in excitatory forebrain neurons using NexCre mice. Electrophysiological...
Source: Acta Neuropathologica - November 28, 2014 Category: Neurology Source Type: research

ATRX and IDH1-R132H immunohistochemistry with subsequent copy number analysis and IDH sequencing as a basis for an “integrated” diagnostic approach for adult astrocytoma, oligodendroglioma and glioblastoma
We present an algorithm based on stepwise analysis with initial immunohistochemistry for ATRX and IDH1-R132H followed by 1p/19q analysis followed by IDH sequencing which reduces the number of molecular analyses and which has a far better association with patient outcome than WHO 2007. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - November 27, 2014 Category: Neurology Source Type: research

Dentate gyrus abnormalities in sudden unexplained death in infants: morphological marker of underlying brain vulnerability
Abstract Sudden unexplained death in infants, including the sudden infant death syndrome, is likely due to heterogeneous causes that involve different intrinsic vulnerabilities and/or environmental factors. Neuropathologic research focuses upon the role of brain regions, particularly the brainstem, that regulate or modulate autonomic and respiratory control during sleep or transitions to waking. The hippocampus is a key component of the forebrain–limbic network that modulates autonomic/respiratory control via brainstem connections, but its role in sudden infant death has received little attention. We tested ...
Source: Acta Neuropathologica - November 25, 2014 Category: Neurology Source Type: research

Collagen VI regulates peripheral nerve regeneration by modulating macrophage recruitment and polarization
Abstract Macrophages contribute to peripheral nerve regeneration and produce collagen VI, an extracellular matrix protein involved in nerve function. Here, we show that collagen VI is critical for macrophage migration and polarization during peripheral nerve regeneration. Nerve injury induces a robust upregulation of collagen VI, whereas lack of collagen VI in Col6a1 −/− mice delays peripheral nerve regeneration. In vitro studies demonstrated that collagen VI promotes macrophage migration and polarization via AKT and PKA pathways. Col6a1 −/− macrophages exhibit impaired ...
Source: Acta Neuropathologica - November 25, 2014 Category: Neurology Source Type: research

The toxic effect of R350P mutant desmin in striated muscle of man and mouse
Abstract Mutations of the human desmin gene on chromosome 2q35 cause autosomal dominant, autosomal recessive and sporadic forms of protein aggregation myopathies and cardiomyopathies. We generated R349P desmin knock-in mice, which harbor the ortholog of the most frequently occurring human desmin missense mutation R350P. These mice develop age-dependent desmin-positive protein aggregation pathology, skeletal muscle weakness, dilated cardiomyopathy, as well as cardiac arrhythmias and conduction defects. For the first time, we report the expression level and subcellular distribution of mutant versus wild-type desmin ...
Source: Acta Neuropathologica - November 13, 2014 Category: Neurology Source Type: research

Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells
In this study, telomerase enzymatic activity was directly measured and inhibited to assess the therapeutic potential of targeting telomerase. Telomerase repeat amplification protocol (TRAP) (n = 36) and C-circle assay/telomere FISH/ATRX staining (n = 76) were performed on primary ependymomas to determine the prevalence and prognostic potential of telomerase activity or alternative lengthening of telomeres (ALT) as telomere maintenance mechanisms, respectively. Imetelstat, a phase 2 telomerase inhibitor, was used to elucidate the effect of telomerase inhibition on proliferation and tumorigenicity in esta...
Source: Acta Neuropathologica - November 13, 2014 Category: Neurology Source Type: research

Very-late-antigen-4 (VLA-4)-mediated brain invasion by neutrophils leads to interactions with microglia, increased ischemic injury and impaired behavior in experimental stroke
Abstract Neuronal injury from ischemic stroke is aggravated by invading peripheral immune cells. Early infiltrates of neutrophil granulocytes and T-cells influence the outcome of stroke. So far, however, neither the timing nor the cellular dynamics of neutrophil entry, its consequences for the invaded brain area, or the relative importance of T-cells has been extensively studied in an intravital setting. Here, we have used intravital two-photon microscopy to document neutrophils and brain-resident microglia in mice after induction of experimental stroke. We demonstrated that neutrophils immediately rolled, fir...
Source: Acta Neuropathologica - November 12, 2014 Category: Neurology Source Type: research

Hypermethylation of repeat expanded C9orf72 is a clinical and molecular disease modifier
Abstract C9orf72 promoter hypermethylation inhibits the accumulation of pathologies which have been postulated to be neurotoxic. We tested here whether C9orf72 hypermethylation is associated with prolonged disease in C9orf72 mutation carriers. C9orf72 methylation was quantified from brain or blood using methylation-sensitive restriction enzyme digest-qPCR in a cross-sectional cohort of 118 C9orf72 repeat expansion carriers and 19 non-carrier family members. Multivariate regression models were used to determine whether C9orf72 hypermethylation was associated with age at onset, disease duration, age at de...
Source: Acta Neuropathologica - November 11, 2014 Category: Neurology Source Type: research

Pathogenic Ubqln2 gains toxic properties to induce neuron death
Abstract Mutations in ubiquilin 2 (Ubqln2) is linked to amyotrophic lateral sclerosis and frontotemporal lobar degeneration. A foremost question regarding Ubqln2 pathogenesis is whether pathogenically mutated Ubqln2 causes neuron death via a gain or loss of functions. To better understand Ubqln2 pathobiology, we created Ubqln2 transgenic and knockout rats and compared phenotypic expression in these novel rat models. Overexpression of Ubqln2 with a pathogenic mutation (P497H substitution) caused cognitive deficits and neuronal loss in transgenic rats at the age of 130 days. In the transgenic rats, neuronal los...
Source: Acta Neuropathologica - November 11, 2014 Category: Neurology Source Type: research

Farewell to oligoastrocytoma: response to letters
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - November 9, 2014 Category: Neurology Source Type: research

PART and SNAP
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - November 8, 2014 Category: Neurology Source Type: research

In vivo markers of Parkinson’s disease and dementia with Lewy bodies: current value of the 5G4 α-synuclein antibody
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - November 7, 2014 Category: Neurology Source Type: research

Hippocampal sclerosis in Lewy body disease is a TDP-43 proteinopathy similar to FTLD-TDP Type A
Abstract Hippocampal sclerosis (HpScl) is frequent in frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), but it also occurs in dementia of the elderly with or without accompanying Alzheimer type pathology. HpScl has been hypothesized to be a neurodegenerative process given its association with TDP-43 pathology, but this is still controversial. TDP-43 pathology is found in Lewy body disease (LBD), but no study has focused on the pathologic and genetic characteristics of HpScl in LBD. We found HpScl in 5.2 % of 669 LBD cases (289 transitional and 380 diffuse). Older age, higher Braak neurofibri...
Source: Acta Neuropathologica - November 4, 2014 Category: Neurology Source Type: research

Autophagy in neuronal cells: general principles and physiological and pathological functions
Abstract Autophagy delivers cytoplasmic components and organelles to lysosomes for degradation. This pathway serves to degrade nonfunctional or unnecessary organelles and aggregate-prone and oxidized proteins to produce substrates for energy production and biosynthesis. Macroautophagy delivers large aggregates and whole organelles to lysosomes by first enveloping them into autophagosomes that then fuse with lysosomes. Chaperone-mediated autophagy (CMA) degrades proteins containing the KFERQ-like motif in their amino acid sequence, by transporting them from the cytosol across the lysosomal membrane into the lysosom...
Source: Acta Neuropathologica - November 4, 2014 Category: Neurology Source Type: research

Formaldehyde-fixed brain tissue from spontaneously ill α-synuclein transgenic mice induces fatal α-synucleinopathy in transgenic hosts
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - November 4, 2014 Category: Neurology Source Type: research

Mixed glioma with molecular features of composite oligodendroglioma and astrocytoma: a true “oligoastrocytoma”?
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - October 31, 2014 Category: Neurology Source Type: research

Are cases with tau pathology occurring in the absence of Aβ deposits part of the AD-related pathological process?
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - October 31, 2014 Category: Neurology Source Type: research

Primary age-related tauopathy (PART): a common pathology associated with human aging
Abstract We recommend a new term, “primary age-related tauopathy” (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer’s disease (AD), in the absence of amyloid (Aβ) plaques. For these “NFT+/Aβ−” brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and ...
Source: Acta Neuropathologica - October 28, 2014 Category: Neurology Source Type: research

Paraneoplastic CDR2 and CDR2L antibodies affect Purkinje cell calcium homeostasis
Abstract Paraneoplastic cerebellar degeneration (PCD) is characterized by loss of Purkinje cells (PCs) associated with progressive pancerebellar dysfunction in the presence of onconeural Yo antibodies. These antibodies recognize the cerebellar degeneration-related antigens CDR2 and CDR2L. Response to PCD therapy is disappointing due to limited understanding of the neuropathological mechanisms. Here, we report the pathological role of CDR antibodies on the calcium homeostasis in PCs. We developed an antibody-mediated PCD model based on co-incubation of cerebellar organotypic slice culture with human patient serum o...
Source: Acta Neuropathologica - October 24, 2014 Category: Neurology Source Type: research

The tumor suppressor prostate apoptosis response-4 (Par-4) is regulated by mutant IDH1 and kills glioma stem cells
Abstract Prostate apoptosis response-4 (Par-4) is an endogenous tumor suppressor that selectively induces apoptosis in a variety of cancers. Although it has been the subject of intensive research in other cancers, less is known about its significance in gliomas, including whether it is regulated by key driver mutations, has therapeutic potential against glioma stem cells (GSCs), and/or is a prognostic marker. We found that patient-derived gliomas with mutant isocitrate dehydrogenase 1 have markedly lower Par-4 expression (P 
Source: Acta Neuropathologica - October 22, 2014 Category: Neurology Source Type: research

Plasma exosomal α-synuclein is likely CNS-derived and increased in Parkinson’s disease
In this study, we discovered, via an intracerebroventricular injection of radiolabeled α-synuclein into mouse brain, that CSF α-synuclein was readily transported to blood, with a small portion being contained in exosomes that are relatively specific to the central nervous system (CNS). Consequently, we developed a technique to evaluate the levels of α-synuclein in these exosomes in individual plasma samples. When applied to a large cohort of clinical samples (267 PD, 215 controls), we found that in contrast to CSF α-synuclein concentrations, which are consistently reported to be lower in PD patients...
Source: Acta Neuropathologica - October 22, 2014 Category: Neurology Source Type: research

Astrocyte-derived retinoic acid: a novel regulator of blood–brain barrier function in multiple sclerosis
Abstract Multiple sclerosis (MS) lesions are characterized by the presence of activated astrocytes, which are thought to actively take part in propagating lesion progression by secreting pro-inflammatory mediators. Conversely, reactive astrocytes may exert disease-dampening effects through the production of trophic factors and anti-inflammatory mediators. Astrocytic control of the blood–brain barrier (BBB) is crucial for normal brain homeostasis and BBB disruption is a well-established early event in MS lesion development. Here, we set out to unravel potential protective effects of reactive astrocytes on BB...
Source: Acta Neuropathologica - October 22, 2014 Category: Neurology Source Type: research

Abnormal serine phosphorylation of insulin receptor substrate 1 is associated with tau pathology in Alzheimer’s disease and tauopathies
This study investigated the expression of abnormal serine phosphorylation of insulin receptor substrate 1 (IRS1) in 157 human brain autopsy cases that included AD, tauopathies, α-synucleinopathies, TDP-43 proteinopathies, and normal aging. IRS1-pS616, IRS1-pS312 and downstream target Akt-pS473 measures were most elevated in AD but were also significantly increased in the tauopathies: Pick’s disease, corticobasal degeneration and progressive supranuclear palsy. Double immunofluorescence labeling showed frequent co-expression of IRS1-pS616 with pathologic tau in neurons and dystrophic neurites. To further investi...
Source: Acta Neuropathologica - October 22, 2014 Category: Neurology Source Type: research

The autophagy/lysosome pathway is impaired in SCA7 patients and SCA7 knock-in mice
Abstract There is still no treatment for polyglutamine disorders, but clearance of mutant proteins might represent a potential therapeutic strategy. Autophagy, the major pathway for organelle and protein turnover, has been implicated in these diseases. To determine whether the autophagy/lysosome system contributes to the pathogenesis of spinocerebellar ataxia type 7 (SCA7), caused by expansion of a polyglutamine tract in the ataxin-7 protein, we looked for biochemical, histological and transcriptomic abnormalities in components of the autophagy/lysosome pathway in a knock-in mouse model of the disease, postmortem...
Source: Acta Neuropathologica - October 22, 2014 Category: Neurology Source Type: research

Cell fusion in the brain: two cells forward, one cell back
Abstract Adult stem cell populations, notably those which reside in the bone marrow, have been shown to contribute to several neuronal cell types in the rodent and human brain. The observation that circulating bone marrow cells can migrate into the central nervous system and fuse with, in particular, cerebellar Purkinje cells has suggested, at least in part, a potential mechanism behind this process. Experimentally, the incidence of cell fusion in the brain is enhanced with age, radiation exposure, inflammation, chemotherapeutic drugs and even selective damage to the neurons themselves. The presence of cell f...
Source: Acta Neuropathologica - October 22, 2014 Category: Neurology Source Type: research

Epigenetic dysregulation: a novel pathway of oncogenesis in pediatric brain tumors
Abstract A remarkably large number of “epigenetic regulators” have been recently identified to be altered in cancers and a rapidly expanding body of literature points to “epigenetic addiction” (an aberrant epigenetic state to which a tumor is addicted) as a new previously unsuspected mechanism of oncogenesis. Although mutations are also found in canonical signaling pathway genes, we and others identified chromatin-associated proteins to be more commonly altered by somatic alterations than any other class of oncoprotein in several subgroups of childhood high-grade brain tumors. Furthermore,...
Source: Acta Neuropathologica - October 22, 2014 Category: Neurology Source Type: research

Bevacizumab treatment induces metabolic adaptation toward anaerobic metabolism in glioblastomas
Abstract Anti-angiogenic therapy in glioblastoma (GBM) has unfortunately not led to the anticipated improvement in patient prognosis. We here describe how human GBM adapts to bevacizumab treatment at the metabolic level. By performing 13C6-glucose metabolic flux analysis, we show for the first time that the tumors undergo metabolic re-programming toward anaerobic metabolism, thereby uncoupling glycolysis from oxidative phosphorylation. Following treatment, an increased influx of 13C6-glucose was observed into the tumors, concomitant to increased lactate levels and a reduction of metabolites associated with the tri...
Source: Acta Neuropathologica - October 17, 2014 Category: Neurology Source Type: research

Mitochondrial fission augments capsaicin-induced axonal degeneration
In this study, we investigated the role of mitochondrial dynamics in capsaicin-induced axonal degeneration. In capsaicin-treated rodent sensory axons, axonal swellings, decreased mitochondrial stationary site length and reduced mitochondrial transport preceded axonal degeneration. Increased axoplasmic Ca2+ mediated the alterations in mitochondrial length and transport. While sustaining mitochondrial transport did not reduce axonal swellings in capsaicin-treated axons, preventing mitochondrial fission by overexpression of mutant dynamin-related protein 1 increased mitochondrial length, retained mitochondrial membrane potent...
Source: Acta Neuropathologica - October 17, 2014 Category: Neurology Source Type: research

Alternative lengthening of telomeres is enriched in, and impacts survival of TP53 mutant pediatric malignant brain tumors
We examined the association of ALT with alterations in genes found to segregate with specific histological phenotypes and with clinical outcome. ALT was detected almost exclusively in malignant tumors (p = 0.001). ALT was highly enriched in primitive neuroectodermal tumors (12 %), choroid plexus carcinomas (23 %) and high-grade gliomas (22 %). Furthermore, in contrast to adult gliomas, pediatric low grade gliomas which progressed to high-grade tumors did not exhibit the ALT phenotype. Somatic but not germline TP53 mutations were highly associated with ALT (p = 1.01 × 1...
Source: Acta Neuropathologica - October 15, 2014 Category: Neurology Source Type: research

Oligoastrocytomas: throwing the baby out with the bathwater?
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - October 11, 2014 Category: Neurology Source Type: research

Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats
In conclusion, we here provide the first experimental evidence that different α-synuclein forms can propagate from the gut to the brain, and that microtubule-associated transport is involved in the translocation of aggregated α-synuclein in neurons. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - October 9, 2014 Category: Neurology Source Type: research

Erratum to: Amyloidogenic α-synuclein seeds do not invariably induce rapid, widespread pathology in mice
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - October 9, 2014 Category: Neurology Source Type: research

Predictive molecular markers in metastases to the central nervous system: recent advances and future avenues
Abstract Metastases to the central nervous system (CNS) are common in several cancer types. For most primary tumors that commonly metastasize to the CNS, molecular biomarker analyses are recommended in the clinical setting for selection of appropriate targeted therapies. Therapeutic efficacy of some of these agents has been documented in patients with brain metastases, and molecular testing of CNS metastases should be considered in the clinical setting. Here, we summarize the clinically relevant biomarker tests that should be considered in neurosurgical specimens based on the current recommendations of the Europea...
Source: Acta Neuropathologica - October 7, 2014 Category: Neurology Source Type: research

The multifaceted nature of amyloid precursor protein and its proteolytic fragments: friends and foes
Abstract The amyloid precursor protein (APP) has occupied a central position in Alzheimer’s disease (AD) pathophysiology, in large part due to the seminal role of amyloid-β peptide (Aβ), a proteolytic fragment derived from APP. Although the contribution of Aβ to AD pathogenesis is accepted by many in the research community, recent studies have unveiled a more complicated picture of APP’s involvement in neurodegeneration in that other APP-derived fragments have been shown to exert pathological influences on neuronal function. However, not all APP-derived peptides are neurotoxic, and some ...
Source: Acta Neuropathologica - October 7, 2014 Category: Neurology Source Type: research

Inflammatory dysregulation of blood monocytes in Parkinson’s disease patients
This study provides insights into monocyte biology in PD and establishes a basis for future studies on peripheral inflammation. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - October 5, 2014 Category: Neurology Source Type: research

Zebrafish models of BAG3 myofibrillar myopathy suggest a toxic gain of function leading to BAG3 insufficiency
Abstract Mutations in the co-chaperone Bcl2-associated athanogene 3 (BAG3) can cause myofibrillar myopathy (MFM), a childhood-onset progressive muscle disease, characterized by the formation of protein aggregates and myofibrillar disintegration. In contrast to other MFM-causing proteins, BAG3 has no direct structural role, but regulates autophagy and the degradation of misfolded proteins. To investigate the mechanism of disease in BAG3-related MFM, we expressed wild-type BAG3 or the dominant MFM-causing BAG3 (BAG3P209L) in zebrafish. Expression of the mutant protein results in the formation of aggregates that cont...
Source: Acta Neuropathologica - October 2, 2014 Category: Neurology Source Type: research

Experimental transmissibility of mutant SOD1 motor neuron disease
Abstract By unknown mechanisms, the symptoms of amyotrophic lateral sclerosis (ALS) seem to spread along neuroanatomical pathways to engulf the motor nervous system. The rate at which symptoms spread is one of the primary drivers of disease progression. One mechanism by which ALS symptoms could spread is by a prion-like propagation of a toxic misfolded protein from cell to cell along neuroanatomic pathways. Proteins that can transmit toxic conformations between cells often can also experimentally transmit disease between individual organisms. To survey the ease with which motor neuron disease (MND) can be transmit...
Source: Acta Neuropathologica - September 28, 2014 Category: Neurology Source Type: research

Is there a risk of prion-like disease transmission by Alzheimer- or Parkinson-associated protein particles?
Abstract The misfolding and aggregation of endogenous proteins in the central nervous system is a neuropathological hallmark of Alzheimer’s disease (AD), Parkinson’s disease (PD), as well as prion diseases. A molecular mechanism referred to as “nucleation-dependent aggregation” is thought to underlie this neuropathological phenomenon. According to this concept, disease-associated protein particles act as nuclei, or seeds, that recruit cellular proteins and incorporate them, in a misfolded form, into their growing aggregate structure. Experimental studies have shown that the aggregation of ...
Source: Acta Neuropathologica - September 25, 2014 Category: Neurology Source Type: research

Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress
Abstract The occurrence of repeat-associated non-ATG (RAN) translation, an atypical form of translation of expanded repeats that results in the synthesis of homopolymeric expansion proteins, is becoming more widely appreciated among microsatellite expansion disorders. Such disorders include amyotrophic lateral sclerosis and frontotemporal dementia caused by a hexanucleotide repeat expansion in the C9ORF72 gene (c9FTD/ALS). We and others have recently shown that this bidirectionally transcribed repeat is RAN translated, and the “c9RAN proteins” thusly produced form neuronal inclusions throughout the ce...
Source: Acta Neuropathologica - September 25, 2014 Category: Neurology Source Type: research

C9orf72 FTLD/ALS-associated Gly-Ala dipeptide repeat proteins cause neuronal toxicity and Unc119 sequestration
Abstract Hexanucleotide repeat expansion in C9orf72 is the most common pathogenic mutation in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite the lack of an ATG start codon, the repeat expansion is translated in all reading frames into dipeptide repeat (DPR) proteins, which form insoluble, ubiquitinated, p62-positive aggregates that are most abundant in the cerebral cortex and cerebellum. To specifically analyze DPR toxicity and aggregation, we expressed DPR proteins from synthetic genes containing a start codon but lacking extensive GGGGCC repeats. Poly-Gly...
Source: Acta Neuropathologica - September 25, 2014 Category: Neurology Source Type: research