Lipid rafts act as a common platform for Aß oligomer-induced Alzheimer’s pathology

Background Amyloid ß protein (Aß) oligomers induce the overproduction of phosphorylated tau and neurodegeneration. These cascades gradually cause cognitive impairment in Alzheimer’s disease (AD). While each pathological event in AD has been studied in detail separately, the spatial and temporal relationships between pathological events in AD remain unclear. Here, we demonstrated that lipid rafts function as a common platform for the pathological cascades of AD. Methods Cellular and synaptosomal lipid rafts were prepared from the brains of Aß amyloid model mice (Tg2576 mice) and double transgenic mice (Tg2576 x TgTauP301L mice) and longitudinally analyzed. Results Aß oligomers, the cellular prion protein (PrPc), and Aß oligomer/PrPc complexes were detected in the lipid rafts. The levels of Fyn, the phosphorylated NR2B subunit of the N-methyl-D-aspartate receptor, glycogen synthase kinase 3 beta, total tau, phosphorylated tau, and tau oligomers increased with Aß oligomer accumulation in both the cellular and synaptosomal lipid rafts. Increases in the levels of these molecules were first seen at 6 months of age and corresponded with the early stages of Aß accumulation in the amyloid model mice. Conclusions Lipid rafts act as a common platform for the progression of Alzheimer’s pathology. The findings of this study suggest a novel therapeutic approach to AD, involving the modification of lipid raft components and the inhibition of their roles in the sequential pathological events of AD.

Necroptosis inhibition counteracts axonal degeneration, cognitive decline and key hallmarks of aging, promoting brain rejuvenation.

Age is the main risk factor for cognitive impairment and the development of neurodegenerative diseases. In the aged brain, axonal degeneration is an early pathological event, preceding neuronal dysfunction and brain disabilities in humans, primates, rodents, and invertebrates. Necroptosis activation mediates degeneration of mechanical and chemically injured axons, but whether this pathway triggers axonal degeneration and cognitive impairment during brain aging has not been studied. Here we show that necroptosis is activated in the hippocampus during aging, especially in axonal tracts. Loss of the main necroptotic effector, Mlkl, was sufficient to delay age-associated axonal degeneration. Accordingly, aged Mlkl-KO mice also displayed a youthful phenotype at the synaptic and functional level, protecting against decreased synaptic transmission and memory decline. Short-term pharmacologic inhibition of necroptosis by targeting RIPK3 in aged mice, proved to be extraordinarily effective at reverting axonal degeneration and hippocampal-dependent functional impairment at the electrophysiological and behavioral level. Remarkably, a comprehensive quantitative proteomic analysis uncovered a set of aging hallmarks that were recovered in both, the genetic and pharmacologic models of necroptosis inhibition, including molecular biofunctions associated with brain rejuvenation. Taken together, these findings demonstrate that necroptosis contributes to the age-associated deterioration of axonal integrity, affecting hippocampal neuronal connectivity and cognitive function in aged individuals. We therefore propose necroptosis as an attractive target for the future development of geroprotective tools to treat age-related disabilities.

The role of pathological tau in synaptic dysfunction in Alzheimer’s diseases

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, accompanied by amyloid-β (Aβ) overload and hyperphosphorylated tau accumulation in the brain. Synaptic dysfunction, an important pathological hallmark in AD, is recognized as the main cause of the cognitive impairments. Accumulating evidence suggests that synaptic dysfunction could be an early pathological event in AD. Pathological tau, which is detached from axonal microtubules and mislocalized into pre- and postsynaptic neuronal compartments, is suggested to induce synaptic dysfunction in several ways, including reducing mobility and release of presynaptic vesicles, decreasing glutamatergic receptors, impairing the maturation of dendritic spines at postsynaptic terminals, disrupting mitochondrial transport and function in synapses, and promoting the phagocytosis of synapses by microglia. Here, we review the current understanding of how pathological tau mediates synaptic dysfunction and contributes to cognitive decline in AD. We propose that elucidating the mechanism by which pathological tau impairs synaptic function is essential for exploring novel therapeutic strategies for AD.

Developing an in-vivo physiological porcine model of inducing acute atraumatic compartment syndrome towards a non-invasive diagnosis using shear wave elastography

Compartment syndrome (CS) is a pathological event caused by elevated intracompartmental pressure (ICP); however, changes from the onset of inducing atraumatic CS remained unclear. The study aimed to investigate the physiological changes in a newly developed in vivo porcine acute atraumatic CS model. CS was induced by ischemia–reperfusion injury in the left hind leg of fourteen pigs divided into an echogenicity group (EG) and a shear wave elastography group (SEG). Echogenicity was measured in EG, and shear elastic modulus (SEM) was measured in SEG seven times before, at the onset of inducing CS, and every 30 min after the onset over eight hours. Simultaneously, ICP, blood pressure, and muscle perfusion pressure (MPP) were also measured in both groups. Our results indicate that SEM of the experimental leg in SEG significantly increased as CS developed compared to the control leg (p = 0.027), but no statistical difference in the echogenicity in EG was found between the experimental leg and control leg. There were also significant correlations between SEM and ICP (p < 0.001) and ICP and MPP (p < 0.001). Our method and findings can be a basis to develop a non-invasive diagnostic tool using a shear wave elastography for atraumatic CS.

Mitochondrial dysfunction in adult midbrain dopamine neurons triggers an early immune response

Dopamine (DA) neurons of the midbrain are at risk to become affected by mitochondrial damage over time and mitochondrial defects have been frequently reported in Parkinson’s disease (PD) patients. However, the causal contribution of adult-onset mitochondrial dysfunction to PD remains uncertain. Here, we developed a mouse model lacking Mitofusin 2 (MFN2), a key regulator of mitochondrial network homeostasis, in adult midbrain DA neurons. The knockout mice develop severe and progressive DA neuron-specific mitochondrial dysfunction resulting in neurodegeneration and parkinsonism. To gain further insights into pathophysiological events, we performed transcriptomic analyses of isolated DA neurons and found that mitochondrial dysfunction triggers an early onset immune response, which precedes mitochondrial swelling, mtDNA depletion, respiratory chain deficiency and cell death. Our experiments show that the immune response is an early pathological event when mitochondrial dysfunction is induced in adult midbrain DA neurons and that neuronal death may be promoted non-cell autonomously by the cross-talk and activation of surrounding glial cells.

A multidisciplinary approach for external cervical resorption: A case report with 5-year follow-up

Introduction: External cervical resorption (ECR) is a physiological or pathological event usually detected on radiographic examination, since there are no symptoms in its initial and intermediate phases. Objectives: This case is an important finding because the early detection of this lesion allowed an effective multidisciplinary approach to be carried out. Case Report: Radiography was taken in a 55-year-old male and revealed a radiolucent area on the distal surface of the permanent mandibular left first molar, suggesting ECR with impaired pulpal vitality. Based on the clinical and radiographic examinations, a multidisciplinary approach was established involving endodontic treatment, periodontal surgery and indirect restoration that provided an option for preserve the affected tooth. The early diagnosis of ECR was essential for the successful treatment in order to maintain the satisfactory function for five-year follow-up. Conclusion: Despite the procedures performed, the idiopathic etiology of the lesion contributed to the appearance of recurrences; however, monitoring and maintenance of the affected tooth proved to be important for the longevity of the treatment.

Restless Legs Syndrome and Sleep-Related Movement Disorders

Normal sleep is characterized by a relative lack of body movements. In a variety of sleep disorders, abnormal movements may result from pathological arousals, whereas in sleep-related movement disorders the movement itself is the pathological event. Sleep-related movement disorders are typically characterized by simple, often repetitive and stereotyped movements that occur at sleep onset or during sleep and may disrupt sleep. These include restless legs syndrome, periodic limb movements, sleep-related bruxism, sleep-related leg cramps, and sleep starts. These are common disorders that may be barely noticed or, as in the case of severe restless legs syndrome, can be life-altering. Proper diagnosis is essential because effective treatments are usually available.

Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice

Disrupted homeostasis of the microtubule binding protein tau is a shared feature of a set of neurodegenerative disorders known as tauopathies. Acetylation of soluble tau is an early pathological event in neurodegeneration. In this work, we find that a large fraction of neuronal tau is degraded by chaperone-mediated autophagy (CMA) whereas, upon acetylation, tau is preferentially degraded by macroautophagy and endosomal microautophagy. Rerouting of acetylated tau to these other autophagic pathways originates, in part, from the inhibitory effect that acetylated tau exerts on CMA and results in its extracellular release. In fact, experimental blockage of CMA enhances cell-to-cell propagation of pathogenic tau in a mouse model of tauopathy. Furthermore, analysis of lysosomes isolated from brains of patients with tauopathies demonstrates similar molecular mechanisms leading to CMA dysfunction. This study reveals that CMA failure in tauopathy brains alters tau homeostasis and could contribute to aggravate disease progression.

Neuroinflammation in Ischemic Stroke: Focus on MicroRNA-mediated Polarization of Microglia

Ischemic stroke is one of the most common causes of death and disability worldwide. Neuroinflammation is a major pathological event involved in the process of ischemic injury and repair. In particular, microglia play a dual role in neuroinflammation. During the acute phase of stroke onset, M2 microglia are the dominant phenotype and exert protective effects on neuronal cells, whereas permanent M1 microglia contribute to prolonged inflammation and are detrimental to brain tissue. Emerging evidence indicates that microRNAs (miRNAs) may have regulatory effects on microglia-associated inflammation. Thus, we briefly reviewed the dynamic response of microglia after a stroke and assessed how specific miRNAs affect the behavior of reactive microglia. We concluded that miRNAs may be useful novel therapeutic targets to improve stroke outcomes and modulate neuroinflammation.

Mitochondrial and Organellar Crosstalk in Parkinson’s Disease

Mitochondrial dysfunction is a well-established pathological event in Parkinson’s disease (PD). Proteins misfolding and its impaired cellular clearance due to altered autophagy/mitophagy/pexophagy contribute to PD progression. It has been shown that mitochondria have contact sites with endoplasmic reticulum (ER), peroxisomes and lysosomes that are involved in regulating various physiological processes. In pathological conditions, the crosstalk at the contact sites initiates alterations in intracellular vesicular transport, calcium homeostasis and causes activation of proteases, protein misfolding and impairment of autophagy. Apart from the well-reported molecular changes like mitochondrial dysfunction, impaired autophagy/mitophagy and oxidative stress in PD, here we have summarized the recent scientific reports to provide the mechanistic insights on the altered communications between ER, peroxisomes, and lysosomes at mitochondrial contact sites. Furthermore, the manuscript elaborates on the contributions of mitochondrial contact sites and organelles dysfunction to the pathogenesis of PD and suggests potential therapeutic targets.