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BACKGROUND Grade V spondylolisthesis, or spondyloptosis, is a complication of high-energy trauma that is most commonly reported at the lumbosacral junction. Sacral intersegmental spondyloptosis is extremely rare. The authors present a case of spondyloptosis of S1 on S2 with a comminuted fracture of S2 and complex fractures of the L4 and L5 transverse processes, resulting in severe stenosis of the lumbosacral nerve roots. OBSERVATIONS The patient was a 70-year-old woman with a history of a fall 3 weeks prior and progressive L5 and S1 radiculopathy. Instrumentation and fusion were undertaken, extending from L3 to the pelvis because degenerative stenosis at L3–4 and L4–5 was also found. Reduction was achieved, leading to diminished pain and partial resolution of weakness. LESSONS Traumatic sacral spondyloptosis adds a degree of difficulty to reduction, fixation, and fusion. The technique presented herein achieved sagittal realignment via a distraction maneuver of S1–2 in which rods were attached to bilateral dual S2 alar-iliac screws with reduction screws placed at S1, ultimately pulling L5 and S1 up to the rod for fixation.

The ExcelsiusGPS (Globus Medical, Inc., Audubon, PA) robot received clearance from the United States Food and Drug Administration for clinical use in 2017 with the first in human use for lumbar spine instrumentation at Johns Hopkins Hospital the same year. The applications of the robot soon expanded with the first interbody cage placement in 2020 and first deep brain stimulation performed in 2021. A metanalysis by Kosmopoulos et al1 found that of 37,337 pedicle screws implanted by freehand, 34,107 (91.3%) were found to be placed accurately. Furthermore, there was a higher rate of accuracy in the navigation group (95.2%) compared to without navigation (90.3%). Initial studies with the ExcelsiusGPS robot reported successful lumbar pedicle screw placement rate of 97.4% (339/348)2 and 99% (555/562).3 The ExcelsiusGPS robot has been shown to increase screw placement accuracy enabling utilization of longer screw length and diameters, reduce radiation exposure and surgical time.4 While conventional uses of the robot in spine surgery are pedicle screw placement and sacroiliac fusion, newer navigated interbody placement software hopes to minimize spinal cord injury during interbody placement. Current use in cranial surgery include biopsy, deep brain stimulation, and stereoelectroencephalography (sEEG). High cervical fixation involving C1 and C2 is a complex surgery with potentially severe complications including screw malposition causing damage to neural and/or vascular structures. In a study evaluating the accuracy of free-hand technique of C2 pars screw placement, 11% of screws were mispositioned using the cortical-breach grading system5. Among high cervical transarticular screws, the most common complication included screw misposition at 7% while vertebral artery injury occurred in about 3% of patients6. It was noted that anatomic constraints for this procedure involve alignment of C1 and C2 while inadequate reduction of C1 and C2 contributed to screw misposition. Due to these complications, higher accuracy is needed. Common complications of depth electrode placement for sEEG are hemorrhage related (eg: subdural hematoma, epidural hematoma or intracerebral hemorrhage) and hardware related complications such as malpositioning, electrode fracture, or electrode-recording malfunction7. Robotic navigation aims to reduce these events and increase accuracy. Here we report the first case series of high cervical fixation and sEEG depth electrode placement using the ExcelsiusGPS robot.

BACKGROUND Placing screws in the high cervical spine can be challenging because of the vital anatomical structures located in that region. Precision and accuracy with screw placement is needed. The use of robotics in the cervical spine has been described before; however, here the authors describe the use of a new robotic setup. OBSERVATIONS The authors describe 2 cases of robot-assisted placement of C2 pars screws and C1–2 transarticular screws. The operative plans for each patient were as follows: placement of C2 pars screws with C2–4 fusion for hangman’s fracture and placement of C1–2 transarticular screws for degenerative disease. Intraoperative computed tomography (CT) was used to plan and navigate the screws. Postoperative CT showed excellent placement of hardware. Both patients presented for initial postoperative clinic visits with no recurrence of prior symptoms. LESSONS Intraoperative robotic assistance with instrumentation of the high cervical spine, particularly C2 pars and C1–2 transarticular screws, may ensure proper screw placement and help avoid injury.

Isthmic spondylolisthesis can be defined as the anterior translation of a vertebral body relative to the one subjacent to it and secondary to an abnormality of the pars interarticularis. Isthmic spondylolisthesis is usually asymptomatic and discovered as an incidental radiographic finding. However, it can be symptomatic due to its biomechanical effects on the adjacent neural structures and patients may present with low back and/or radicular leg pain. Standing plain radiographs can be obtained to confirm the presence or assess the degree of isthmic spondylolisthesis. Computed tomography (CT) clearly shows the pars defect and provides a better assessment of the pathology. Magnetic resonance imaging (MRI) is indicated in patients with neurologic manifestations and can be used to assess the degree of foraminal or central stenosis. Conservative management including oral anti-inflammatory medication, physical therapy, and/or transforaminal epidural corticosteroid injections can be utilized initially. Surgery can be considered in the setting of persistent symptoms unrelieved with conservative management or significant neurologic compromise. Several surgical methods and techniques are available in the management of isthmic spondylolisthesis. There has been a significant national increase in the use of interbody fusion posteriorly for the management of isthmic spondylolisthesis. Reports have suggested that interbody fusion can be a cost-effective technique in selected patients with isthmic spondylolisthesis. Future studies are encouraged to further characterize the specific indications of various surgical modalities in patients with isthmic spondylolisthesis.

Background and importance En bloc resection of sacral tumors is the most effective treatment to help prevent recurrence. Sacrectomy, however, can be destabilizing, depending on the extent of resection. Various surgical techniques for improving stability and enabling early ambulation have been proposed. Clinical presentation Here, we report a case in which we use PMMA (poly[methyl methacrylate]) to augment pelvic instrumentation to improve mechanical stability after sacrectomy for en bloc resection of a solitary fibrous tumor. Conclusion We highlight the use of sacroplasty augmentation of pelvic ring reconstruction to provide biomechanical stability without the need for fusion of any mobile spine segments, which allowed for early patient ambulation and no appreciable loss of range of motion or mobility.

This was a systematic review of the literature.The aim was to examine the contemporary demographics, etiological factors, treatment options and outcomes of spinal epidural lipomatosis (SEL) in adults.SEL is primarily seen in obese patients as well as those on steroid therapy. Much regarding the etiology and treatment outcomes of SEL is unknown.We reviewed Ovid MEDLINE, PubMed, SCOPUS, and Google Scholars databases from 1990 through August 2020 to identify cases of SEL. Data collected included patient characteristics, disease associations, level of pathology, treatment, and clinical outcomes.Ninety articles (145 individual cases) were included in the analysis. The median age was 54 years and 79% were males. Obesity-associated SEL constituted the largest proportion (52%) of our cohort. 22% of SEL cases were related to steroid use, while 26% cases were considered to be idiopathic. Lumbosacral SEL was the most frequently reported level of disease (68.9%), followed by the thoracic level (26.2%). The mean age of cases who underwent surgical intervention was 55 years, as compared with 48 years in those who received conservative management ( P =0.03). 95% of patients reported some degree of symptomatic improvement regardless of the treatment modality. Logistic regression suggested a possible superior outcome associated with those undergoing surgical treatment.In contrast to historical comparisons, contemporary articles support that obesity has become the major contributing factor for SEL. Logistic regression of the existing cases suggests that there may be a role for surgical intervention in select patients.

α-synuclein (αS) is the major component of several types of brain pathological inclusions that define neurodegenerative diseases termed synucleinopathies. Central nervous system (CNS) inoculation studies using either in vitro polymerized αS fibrils or in vivo derived lysates containing αS aggregates to induce the progressive spread of αS inclusion pathology in animal disease models have supported the notion that αS mediated progressive neurodegeneration can occur by a prion-like mechanism. We have previously shown that neonatal brain inoculation with preformed αS fibrils in hemizygous M20+/− transgenic mice expressing wild type human αS and to a lesser extent in non-transgenic mice can result in a concentration-dependent progressive induction of CNS αS pathology. Recent studies using brain lysates from patients with multiple system atrophy (MSA), characterized by αS inclusion pathology in oligodendrocytes, indicate that these may be uniquely potent at inducing αS pathology with prion-like strain specificity. We demonstrate here that brain lysates from MSA patients, but not control individuals, can induce αS pathology following neonatal brain inoculation in transgenic mice expressing A53T human αS (M83 line), but not in transgenic expressing wild type human αS (M20 line) or non-transgenic mice within the timeframe of the study design. Further, we show that neuroanatomical and immunohistochemical properties of the pathology induced by MSA brain lysates is very similar to what is produced by the neonatal brain injection of preformed human αS fibrils in hemizygous M83+/− transgenic mice. Collectively, these findings reinforce the idea that the intrinsic traits of the M83 mouse model dominates over any putative prion-like strain properties of MSA αS seeds that can induce pathology. Electronic supplementary material The online version of this article (10.1186/s40478-019-0733-3) contains supplementary material, which is available to authorized users.

Progression of α-synuclein inclusion pathology may occur through cycles of release and uptake of α-synuclein aggregates, which induce additional intracellular α-synuclein inclusion pathology. This process may explain (i) the presence of α-synuclein inclusion pathology in grafted cells in human brains, and (ii) the slowly progressive nature of most human α-synucleinopathies. It also provides a rationale for therapeutic targeting of extracellular aggregates to limit pathology spread. We investigated the cellular mechanisms underlying intraneuronal α-synuclein aggregation following exposure to exogenous preformed α-synuclein amyloid fibrils. Exogenous α-synuclein fibrils efficiently attached to cell membranes and were subsequently internalized and degraded within the endosomal/lysosomal system. However, internalized α-synuclein amyloid fibrils can apparently overwhelm the endosomal/lysosomal machinery leading to the induction of intraneuronal α-synuclein inclusions comprised of endogenous α-synuclein. Furthermore, the efficiency of inclusion formation was relatively low in these studies compared to studies using primary neuronal-glial cultures over-expressing α-synuclein. Our study indicates that under physiologic conditions, endosomal/lysosomal function acts as an endogenous barrier to the induction of α-synuclein inclusion pathology, but when compromised, it may lower the threshold for pathology induction/transmission. Cover Image for this issue: doi: 10.1111/jnc.13787.

Mechanisms underlying α-synuclein (αSyn) mediated neurodegeneration are poorly understood. Intramuscular (IM) injection of αSyn fibrils in human A53T transgenic M83+/− mice produce a rapid model of α-synucleinopathy with highly predictable onset of motor impairment. Using varying doses of αSyn seeds, we show that αSyn-induced phenotype is largely dose-independent. We utilized the synchrony of this IM model to explore the temporal sequence of αSyn pathology, neurodegeneration and neuroinflammation. Longitudinal tracking showed that while motor neuron death and αSyn pathology occur within 2 months post IM, astrogliosis appears at a later timepoint, implying neuroinflammation is a consequence, rather than a trigger, in this prionoid model of synucleinopathy. Initiating at 3 months post IM, immune activation dominates the pathologic landscape in terminal IM-seeded M83+/− mice, as revealed by unbiased transcriptomic analyses. Our findings provide insights into the role of neuroinflammation in αSyn mediated proteostasis and neurodegeneration, which will be key in designing potential therapies.

Intracerebral injection of amyloidogenic α-synuclein (αS) has been shown to induce αS pathology in the CNS of nontransgenic mice and αS transgenic mice, albeit with varying efficiencies. In this study, using wild-type human αS transgenic mice (line M20), we demonstrate that intracerebral injection of recombinant amyloidogenic or soluble αS induces extensive αS intracellular inclusion pathology that is associated with robust gliosis. Near the injection site, a significant portion of αS inclusions are detected in neurons but also in astrocytes and microglia. Aberrant induction of expression of the intermediate filament protein peripherin, which is associated with CNS neuronal injury, was also observed predominantly near the site of injection. In addition, many pSer129 αS-induced inclusions colocalize with the low-molecular-mass neurofilament subunit (NFL) or peripherin staining. αS inclusion pathology was also induced in brain regions distal from the injection site, predominantly in neurons. Unexpectedly, we also find prominent p62-immunoreactive, αS-, NFL-, and peripherin-negative inclusions. These findings provide evidence that exogenous αS challenge induces αS pathology but also results in the following: (1) a broader disruption of proteostasis; (2) glial activation; and (3) a marker of a neuronal injury response. Such data suggest that induction of αS pathology after exogenous seeding may involve multiple interdependent mechanisms.

It has been hypothesized that α-synuclein (αS) misfolding may begin in peripheral nerves and spread to the central nervous system (CNS), leading to Parkinson disease and related disorders. Although recent data suggest that αS pathology can spread within the mouse brain, there is no direct evidence for spread of disease from a peripheral site. In the present study, we show that hind limb intramuscular (IM) injection of αS can induce pathology in the CNS in the human Ala53Thr (M83) and wild-type (M20) αS transgenic (Tg) mouse models. Within 2-3 mo after IM injection in αS homozygous M83 Tg mice and 3-4 mo for hemizygous M83 Tg mice, these animals developed a rapid, synchronized, and predictable induction of widespread CNS αS inclusion pathology, accompanied by astrogliosis, microgliosis, and debilitating motor impairments. In M20 Tg mice, starting at 4 mo after IM injection, we observed αS inclusion pathology in the spinal cord, but motor function remained intact. Transection of the sciatic nerve in the M83 Tg mice significantly delayed the appearance of CNS pathology and motor symptoms, demonstrating the involvement of retrograde transport in inducing αS CNS inclusion pathology. Outside of scrapie-mediated prion disease, to our knowledge, this findiing is the first evidence that an entire neurodegenerative proteinopathy associated with a robust, lethal motor phenotype can be initiated by peripheral inoculation with a pathogenic protein. Furthermore, this facile, synchronized rapid-onset model of α-synucleinopathy will be highly valuable in testing disease-modifying therapies and dissecting the mechanism(s) that drive αS-induced neurodegeneration.

Intercellular prion-like transmission of misfolded and aggregated tau protein along interconnected anatomic pathways is thought to contribute to the etiology of tauopathies, such as Alzheimer’s disease (AD) [4]. Indeed, the observation that synthetic tau fibrils and AD patient brain homogenates are capable of inducing robust tau pathology in tau transgenic mice strongly support the hypothesis that exogenous tau can trigger tauopathy by prion-like templating and transmission [1–3,6]. Transmission of tauopathy seems to depend on the molecular conformation of the exogenous seeds [8]. Therefore, characterizing the differential seeding and transmission properties of tau conformers will allow us to determine optimal therapeutics against tauopathies. Here, we evaluated the seeding and transmission properties of pre-fibrillized wild type K18 tau fragment which contains all four microtubule binding domains of the longest tau isoform and retains the amyloid fibril core [9]. Since sonication potentiates prion seeding [7], we investigated the seeding properties of K18 fibrils sonicated either 1) in a low-power water bath sonicator (“Bath”) yielding typical shorter fibrillar preparations or 2) with a metal probe sonicator (“Probe”) resulting predominantly in amorphous aggregates as observed by negative staining electron microscopy (Supplementary Figure 1). Using HEK293T cells overexpressing tau, we demonstrated that both types of sonicated K18 fibrils could efficiently induce intracellular detergent-insoluble tau inclusions in the presence of lipofectamine (Supplementary Figure 2). Next, we tested whether sonicated K18 fibrils induce tauopathy in homozygous JNPL3 tau transgenic mice expressing P301L tau (hP301L) (Supplementary Table 1) [5]. The protracted nature of disease progression makes the hP301L mice an excellent primed model to study seeding and transmission of tauopathy [5]. Sonicated K18 fibrils was bilaterally injected in the hippocampus of 2-month old hP301L mice and analyzed after 4 months. In female hP301L mice, probe-sonicated K18 fibrils, but not bath-sonicated fibrils, induced limited AT8 and PHF1 immunoreactive tau pathology directly at the injection site (hippocampus) and in the neuro-anatomically connected entorhinal cortex (arrows, Figure 1; Supplementary Figure 3). Tau pathology, typically observed in aged hP301L mice, was observed in the brainstem and midbrain of all mice, irrespective of injection. Male hP301L mice similarly injected in the hippocampus with probe-sonicated K18 fibrils failed to show any induction of tau pathology (Supplementary Figure 4). Since hP301L mice develop early spinal cord and brainstem tau pathology [5], we reasoned that if K18 fibrils trigger templated tau protein transmission depending on focal priming, injection of seeds in the gastrocnemius muscle (IM) or cisterna magna (ICM) might induce or potentiate tau pathology following projections along the spinal cord and brainstem. IM or ICM injection of sonicated K18 (water-bath and probe sonicated) fibrils did not result in increased tau pathology in the CNS, suggesting inefficient peripheral to central transmission of tauopathy (Supplementary Figures 5–6). Figure 1 Hippocampal injection of probe-sonicated K18 induces limited tauopathy in female hP301L mice. hP301L mice were bilaterally injected in the hippocampus (arrowhead, top panel) with K18 fibrils sonicated using a bath or probe sonicator, or PBS and analyzed ... In summary, we have demonstrated that though a) synthetic K18 aggregates display robust seeding in vitro, b) intra-hippocampal administration of probe-sonicated K18 fibrils lead to limited induction of tau pathology, and c) peripheral administration of K18 tau does not induce CNS tau pathology in hP301L mice. Our data suggests that significant physio-chemical barriers, dependent on factors such as physical proximity to the injection site and conformation of seeds used, regulates induction of tau pathology in hP301L mice. Our studies seemingly differ from a recent observation of robust tauopathy induction in P301L transgenic mice using K18/PL seeds [6] but these discrepancies may be explained by differences in the type (wild type K18 or K18/PL) and conformation of tau seeds used. Such intriguing observations raise further notions regarding differential transmission properties of tau conformers as well as the acceptor mouse model, ostensibly contributing to distinct physio-chemical properties of tau seeds as suggested by other groups [8]. Based on our data, we speculate that tau inclusion pathology follows a non-stochastic process where conformationally distinct misfolded tau fibrils with specific clinico-pathologic properties display differential seeding potential, perhaps leading to phenotypic diversity of tauopathies [8]. Overall, K18 seeding and spread of tau pathology is an inefficient process in the hP301L primed tau mouse model, highlighting the complex nature of intercellular transmission of tauopathy. These findings should stimulate further studies in harnessing the endogenous mechanisms that can modify or even impede the induction and transmission of tau pathology.

identity of the inducing factor(s) in tissue homogenates has not been unequivocally resolved. To determine whether degenerating tissues might contain non-αS components that could induce pathology in M83+/− mice, we conducted brain injections of young M83+/− mice with spinal cord (SC) homogenates prepared from motor-impaired M83+/+ mice, motor-impaired transgenic mice expressing the G93A variant of human superoxide dismutase-1 (hSOD-1), and healthy non-transgenic (NTg) mice. The intracerebral (hippocampal) injection of SC homogenates from affected M83+/+ mice served as a positive control and these mice were sacrificed at 120 days post-injection (DPI), at which time αS pathology was predominantly observed in the forebrain (hippocampus and entorhinal cortex), but also distributed in the midbrain, brainstem, and SC (Supplemental Fig. 1; Table 1). For the intrahippocampal injections of SC homogenates from paralyzed G93A hSOD-1 and NTg mice, the study design was to sacrifice mice at 180 DPI to assess pathology levels. Unexpectedly, two of the M83+/− mice injected with SC homogenate from paralyzed G93A hSOD-1 mice developed motor impairments prior to 180 DPI, leading to complete hind limb paralysis (Table 1). These two mice and the other three asymptomatic mice, sacrificed at 180 DPI, all had prominent αS inclusion pathology with a distribution typical of aged M83 mice, with additional pathology observed in the hippocampus (Fig. 1; Table 1). Even more surprisingly, 4 out of the 5 M83+/− mice injected in the hippocampus with SC homogenates from NTg mice also developed M83-type motor impairment and paralysis (Table 1). M83+/− mice injected with either G93A hSOD-1 or NTg SC homogenates showed similar levels of αS inclusion pathology (Fig. 1; Table 1). One pre-symptomatic mouse from each of these cohorts was sacrificed at 105 DPI to survey for earlier pathologic induction and these also presented with αS inclusion The injection of tissue homogenates from diseased animals into naive animals to induce a neurodegenerative phenotype is a feature that defines “prion-like” transmission. Several recent studies have demonstrated that transgenic mice expressing human A53T-α-synuclein (αS; Line M83), respond to injections of CNS tissue homogenates containing abundant αS pathology by accelerated onset of CNS pathology with concurrent accelerated motor impairment [1, 3–5, 9]. Homozygous line M83+/+ A53T αS mice naturally develop a severe motor phenotype between 8 and 16 months that is associated with the formation of αS inclusions in the spinal cord, brain stem, thalamus, periaqueductal gray, and motor cortex [2]. Hemizygous M83+/− mice do not begin to develop these phenotypes until 21 months or later [2], but disease can be induced earlier by injection of CNS homogenates from affected M83+/+ mice [5, 9]. Although purified αS protein fibrils can reproduce the effects seen with tissue homogenates [1, 3, 6, 8], the

Cephalohematomas in newborns are often managed nonsurgically and resolve within the first month of life. In cases of large hematomas (>7 cm) with delayed resorption and persistence over 4 weeks, these masses can often lead to complications of calcification, infection, or hyperbilirubinemia. We report a case of a 14-day-old child with a persistent, large, noncalcified cephalohematoma. After observation alone showed that the cephalohematoma increased in size, 100 ml of old blood was surgically evacuated on day 15 of life. The procedure required a small 1-cm incision and, unlike most large cephalohematomas evacuated after 1 month of observation, there were no signs of skull-deforming calcification observed. This case report presents the earliest evacuation of large noncalcified cephalohematomas in newborns ever reported in the literature, and suggests benefits of early surgical evacuation before 1 month of life.

Background UBQLN2 mutations have recently been associated with familial forms of amyotrophic lateral sclerosis (ALS) and ALS-dementia. UBQLN2 encodes for ubiquilin-2, a member of the ubiquitin-like protein family which facilitates delivery of ubiquitinated proteins to the proteasome for degradation. To study the potential role of ubiquilin-2 in ALS, we used recombinant adeno-associated viral (rAAV) vectors to express UBQLN2 and three of the identified ALS-linked mutants (P497H, P497S, and P506T) in primary neuroglial cultures and in developing neonatal mouse brains. Results In primary cultures rAAV2/8-mediated expression of UBQLN2 mutants resulted in inclusion bodies and insoluble aggregates. Intracerebroventricular injection of FVB mice at post-natal day 0 with rAAV2/8 expressing wild type or mutant UBQLN2 resulted in widespread, sustained expression of ubiquilin-2 in brain. In contrast to wild type, mutant UBQLN2 expression induced significant pathology with large neuronal, cytoplasmic inclusions and ubiquilin-2-positive aggregates in surrounding neuropil. Ubiquilin-2 inclusions co-localized with ubiquitin, p62/SQSTM, optineurin, and occasionally TDP-43, but were negative for α-synuclein, neurofilament, tau, and FUS. Mutant UBLQN2 expression also resulted in Thioflavin-S-positive inclusions/aggregates. Mice expressing mutant forms of UBQLN2 variably developed a motor phenotype at 3–4 months, including nonspecific clasping and rotarod deficits. Conclusions These findings demonstrate that UBQLN2 mutants (P497H, P497S, and P506T) induce proteinopathy and cause behavioral deficits, supporting a “toxic” gain-of-function, which may contribute to ALS pathology. These data establish also that our rAAV model can be used to rapidly assess the pathological consequences of various UBQLN2 mutations and provides an agile system to further interrogate the molecular mechanisms of ubiquilins in neurodegeneration.

In order to further evaluate the parameters whereby intracerebral administration of recombinant α-synuclein (αS) induces pathological phenotypes in mice, we conducted a series of studies where αS fibrils were injected into the brains of M83 (A53T) and M47 (E46K) αS transgenic (Tg) mice, and non-transgenic (nTg) mice. Using multiple markers to assess αS inclusion formation, we find that injected fibrillar human αS induced widespread cerebral αS inclusion formation in the M83 Tg mice, but in both nTg and M47 Tg mice, induced αS inclusion pathology is largely restricted to the site of injection. Furthermore, mouse αS fibrils injected into nTg mice brains also resulted in inclusion pathology restricted to the site of injection with no evidence for spread. We find no compelling evidence for extensive spread of αS pathology within white matter tracts, and we attribute previous reports of white matter tract spreading to cross-reactivity of the αS pSer129/81A antibody with phosphorylated neurofilament subunit L. These studies suggest that, with the exception of the M83 Tg mice which appear to be uniquely susceptible to induction of inclusion pathology by exogenous forms of αS, there are significant barriers in mice to widespread induction of αS pathology following intracerebral administration of amyloidogenic αS.

SummaryAnti-inflammatory strategies are proposed to have beneficial effects in Alzheimer’s disease. To explore how anti-inflammatory cytokine signaling affects Aβ pathology, we investigated the effects of adeno-associated virus (AAV2/1)-mediated expression of Interleukin (IL)-10 in the brains of APP transgenic mouse models. IL-10 expression resulted in increased Aβ accumulation and impaired memory in APP mice. A focused transcriptome analysis revealed changes consistent with enhanced IL-10 signaling and increased ApoE expression in IL-10-expressing APP mice. ApoE protein was selectively increased in the plaque-associated insoluble cellular fraction, likely because of direct interaction with aggregated Aβ in the IL-10-expressing APP mice. Ex vivo studies also show that IL-10 and ApoE can individually impair glial Aβ phagocytosis. Our observations that IL-10 has an unexpected negative effect on Aβ proteostasis and cognition in APP mouse models demonstrate the complex interplay between innate immunity and proteostasis in neurodegenerative diseases, an interaction we call immunoproteostasis.

Background α-Synuclein (αS) is the major component of several types of brain inclusions including Lewy bodies, a hallmark of Parkinson’s disease. Aberrant aggregation of αS also is associated with cellular demise in multiple neurologic disorders collectively referred to as synucleinopathies. Recent studies demonstrate the induction of αS pathology by a single intracerebral injection of exogenous amyloidogenic αS in adult non-transgenic and transgenic mice expressing human αS. To further investigate the mechanism of pathology induction and evaluate an experimental paradigm with potential for higher throughput, we performed similar studies in neonatal mice injected with αS. Results In non-transgenic mice, we observed limited induction of neuronal αS inclusions predominantly 8 months after brain injection of aggregated, amyloidogenic human αS. More robust inclusion pathology was induced in transgenic mice expressing wild-type human αS (line M20), and inclusion pathology was observed at earlier time points. Injection of a non-amyloidogenic (Δ71-82) deletion protein of αS was also able to induce similar pathology in a subset of M20 transgenic mice. M20 transgenic mice injected with amyloidogenic or non-amyloidogenic αS demonstrated a delayed and robust induction of brain neuroinflammation that occurs in mice with or without αS pathological inclusions implicating this mechanism in aggregate formation. Conclusions The finding that a non-amyloidogenic Δ71-82 αS can induce pathology calls into question the simple interpretation that exogenous αS catalyzes aggregation and spread of intracellular αS pathology solely through a nucleation dependent conformational templating mechanism. These results indicate that several mechanisms may act synergistically or independently to promote the spread of αS pathology.

Background Genetic studies have established a causative role for α-synuclein (αS) in Parkinson’s disease (PD), and the presence of αS aggregates in the form of Lewy body (LB) and Lewy neurite (LN) protein inclusions are defining pathological features of PD. Recent data has established that extracellular αS aggregates can induce intracellular αS pathologies supporting the hypothesis that αS pathology can spread via a “prion-like” self-templating mechanism. Results Here we investigated the potential for conformational templating of αS intracellular aggregates by seeding using recombinant wild-type and PD-linked mutant (A53T and E46K) αS in primary mixed neuronal-glial cultures. We find that wild-type and A53T αS fibrils predominantly seed flame-like inclusions in both neurons and astrocytes of mixed primary cultures; whereas the structurally distinct E46K fibrils seed punctate, rounded inclusions. Notably, these differences in seeded inclusion formation in these cultures reflect differences in inclusion pathology seen in transgenic mice expressing the A53T or E46K αS mutants. We further show that the inclusion morphology is dictated primarily by the seed applied rather than the form of αS expressed. We also provide initial evidence that αS inclusion pathology can be passaged in primary astrocyte cultures. Conclusion These studies establish for the first time that αS aggregation in cultured cells can occur by a morphological self-templating mechanism.

Parkinson's disease, the most common movement disorder, results in an insidious reduction for patients in quality of life and ability to function. A hallmark of Parkinson's disease is the brain accumulation of neuronal cytoplasmic inclusions comprised of the protein α-synuclein. The presence of α-synuclein brain aggregates is observed in several neurodegenerative diseases, including dementia with Lewy bodies and Lewy body variant of Alzheimer's disease. These disorders, as a group, are termed synucleinopathies. Mounting evidence indicates that α-synuclein amyloid pathology may spread during disease progression by a prion-like (self-templating alteration in protein conformation) mechanism. Clear in vitro and cell culture data demonstrate that amyloidogenic α-synuclein can readily induce the conversion of other α-synuclein molecules into this conformation. Some data from experimental mouse studies and autopsied brain analyses also are consistent with the notion that a self-promoting process of α-synuclein amyloid inclusion formation may lead to a progressive spread of disease in vivo. However, as pointed out in this review, there are alternative explanations and interpretations for these findings. Therefore, from a therapeutic perspective, it is critical to determine the relative importance and contribution of α-synuclein prionlike spread in disease before embarking on elaborate efforts to target this putative pathogenic mechanism.

In our original paper, the rows of images in Fig. 1b were inverted and the bottom right (pSer129 stained) image was from the hypothalamic region and not the brainstem region as indicated in the figure legend. We have now correctly rearranged the rows of images to correspond with the text in the figure. We have also replaced the pSer129 immunostained image from the symptomatic, aging M83 mouse to reflect a region in the brainstem as indicated in the original legend.

Background Parkinson’s disease (PD) is a progressive neurodegenerative disorder that is pathologically characterized by loss of dopaminergic neurons from the substantia nigra, the presence of aggregated α-synuclein (αS) and evidence of neuroinflammation. Experimental studies have shown that the cerebral injection of recombinant fibrillar αS, especially in αS transgenic mouse models, can induce the formation and spread of αS inclusion pathology. However, studies reporting this phenomenon did not consider the presence of lipopolysaccharide (LPS) in the injected αS, produced in E. coli, as a potential confound. The objectives of this study are to develop a method to remove the LPS contamination and investigate the differences in pathologies induced by αS containing LPS or αS highly purified of LPS. Results and conclusions We were able to remove >99.5 % of the LPS contamination from the αS preparations through the addition of a cation exchange step during purification. The αS pathology induced by injection of fibrils produced from αS containing LPS or purified of LPS, showed a similar distribution pattern; however, there was less spread into the cortex of the mice injected with αS containing higher levels of LPS. As previously reported, injection of αS fibrils could induce astrogliosis, and αS inclusions were present within astrocytes in mice injected with fibrils comprised of αS with or without cation exchange purification. Furthermore, we identified the presence of αS pathology in ependymal cells in both groups of mice, which suggests the involvement of a novel mechanism for spread in this model of αS pathology. Electronic supplementary material The online version of this article (doi:10.1186/s13024-015-0029-4) contains supplementary material, which is available to authorized users.