Apolipoprotein E aggregation in microglia initiates Alzheimer's disease pathology by seeding β-amyloidosis.

The seeded growth of pathogenic protein aggregates underlies the pathogenesis of Alzheimer's disease (AD), but how this pathological cascade is initiated is not fully understood. Sporadic AD is linked genetically to apolipoprotein E (APOE) and other genes expressed in microglia related to immune, lipid, and endocytic functions. We generated a transgenic knockin mouse expressing HaloTag-tagged APOE and optimized experimental protocols for the biochemical purification of APOE, which enabled us to identify fibrillary aggregates of APOE in mice with amyloid-β (Aβ) amyloidosis and in human AD brain autopsies.

Remember oligodendrocytes: Uncovering their overlooked role in Alzheimer's disease.

Our understanding of Alzheimer's disease (AD) has evolved from focusing solely on neurons to recognizing the role of glia. A recent study in PLOS Biology revealed that oligodendrocytes are an important source of Aβ that impairs neuronal function.

Oligodendrocytes produce amyloid-β and contribute to plaque formation alongside neurons in Alzheimer's disease model mice.

Amyloid-β (Aβ) is thought to be neuronally derived in Alzheimer's disease (AD). However, transcripts of amyloid precursor protein (APP) and amyloidogenic enzymes are equally abundant in oligodendrocytes (OLs). By cell-type-specific deletion of Bace1 in a humanized knock-in AD model, APP, we demonstrate that OLs and neurons contribute to Aβ plaque burden.

T cell-mediated microglial activation triggers myelin pathology in a mouse model of amyloidosis.

Age-related myelin damage induces inflammatory responses, yet its involvement in Alzheimer's disease remains uncertain, despite age being a major risk factor. Using a mouse model of Alzheimer's disease, we found that amyloidosis itself triggers age-related oligodendrocyte and myelin damage. Mechanistically, CD8 T cells promote the progressive accumulation of abnormally interferon-activated microglia that display myelin-damaging activity.

Peripheral expression of brain-penetrant progranulin rescues pathologies in mouse models of frontotemporal lobar degeneration.

Progranulin (PGRN) haploinsufficiency is a major risk factor for frontotemporal lobar degeneration with TAR DNA-binding protein 43 (TDP-43) pathology (FTLD-). Multiple therapeutic strategies are in clinical development to restore PGRN in the CNS, including gene therapy. However, a limitation of current gene therapy approaches aimed to alleviate FTLD-associated pathologies may be their inefficient brain exposure and biodistribution.

Nedd4-2-dependent regulation of astrocytic Kir4.1 and Connexin43 controls neuronal network activity.

Nedd4-2 is an E3 ubiquitin ligase in which missense mutation is related to familial epilepsy, indicating its critical role in regulating neuronal network activity. However, Nedd4-2 substrates involved in neuronal network function have yet to be identified. Using mouse lines lacking Nedd4-1 and Nedd4-2, we identified astrocytic channel proteins inwardly rectifying K+ channel 4.

Myelin dysfunction drives amyloid-β deposition in models of Alzheimer's disease.

The incidence of Alzheimer's disease (AD), the leading cause of dementia, increases rapidly with age, but why age constitutes the main risk factor is still poorly understood. Brain ageing affects oligodendrocytes and the structural integrity of myelin sheaths, the latter of which is associated with secondary neuroinflammation. As oligodendrocytes support axonal energy metabolism and neuronal health, we hypothesized that loss of myelin integrity could be an upstream risk factor for neuronal amyloid-β (Aβ) deposition, the central neuropathological hallmark of AD.

Ketogenic diet uncovers differential metabolic plasticity of brain cells.

To maintain homeostasis, the body, including the brain, reprograms its metabolism in response to altered nutrition or disease. However, the consequences of these challenges for the energy metabolism of the different brain cell types remain unknown. Here, we generated a proteome atlas of the major central nervous system (CNS) cell types from young and adult mice, after feeding the therapeutically relevant low-carbohydrate, high-fat ketogenic diet (KD) and during neuroinflammation.

Local cholesterol metabolism orchestrates remyelination.

Cholesterol is an essential component of all cell membranes and particularly enriched in myelin membranes. Myelin membranes are a major target of immune attacks in the chronic neurological disorder multiple sclerosis (MS). During demyelinating insults, cholesterol is released from damaged myelin, increasing local levels of this unique lipid and impeding tissue regeneration.

NMDAR1 autoantibodies amplify behavioral phenotypes of genetic white matter inflammation: a mild encephalitis model with neuropsychiatric relevance.

Encephalitis has an estimated prevalence of ≤0.01%. Even with extensive diagnostic work-up, an infectious etiology is identified or suspected in <50% of cases, suggesting a role for etiologically unclear, noninfectious processes.

Neuronal cholesterol synthesis is essential for repair of chronically demyelinated lesions in mice.

Astrocyte-derived cholesterol supports brain cells under physiological conditions. However, in demyelinating lesions, astrocytes downregulate cholesterol synthesis, and the cholesterol that is essential for remyelination has to originate from other cellular sources. Here, we show that repair following acute versus chronic demyelination involves distinct processes.

Anesthesia triggers drug delivery to experimental glioma in mice by hijacking caveolar transport.

Background: Pharmaceutical intervention in the CNS is hampered by the shielding function of the blood-brain barrier (BBB). To induce clinical anesthesia, general anesthetics such as isoflurane readily penetrate the BBB. Here, we investigated whether isoflurane can be utilized for therapeutic drug delivery.

Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis.

The repair of inflamed, demyelinated lesions as in multiple sclerosis (MS) necessitates the clearance of cholesterol-rich myelin debris by microglia/macrophages and the switch from a pro-inflammatory to an anti-inflammatory lesion environment. Subsequently, oligodendrocytes increase cholesterol levels as a prerequisite for synthesizing new myelin membranes. We hypothesized that lesion resolution is regulated by the fate of cholesterol from damaged myelin and oligodendroglial sterol synthesis.

Liver kinase B1 depletion from astrocytes worsens disease in a mouse model of multiple sclerosis.

Liver kinase B1 (LKB1) is a ubiquitously expressed kinase involved in the regulation of cell metabolism, growth, and inflammatory activation. We previously reported that a single nucleotide polymorphism in the gene encoding LKB1 is a risk factor for multiple sclerosis (MS). Since astrocyte activation and metabolic function have important roles in regulating neuroinflammation and neuropathology, we examined the serine/threonine kinase LKB1 in astrocytes in a chronic experimental autoimmune encephalomyelitis mouse model of MS.

Correction to: Ketogenic diet ameliorates axonal defects and promotes myelination in Pelizaeus-Merzbacher disease.

The original article was published.

Ketogenic diet ameliorates axonal defects and promotes myelination in Pelizaeus-Merzbacher disease.

Pelizaeus-Merzbacher disease (PMD) is an untreatable and fatal leukodystrophy. In a model of PMD with perturbed blood-brain barrier integrity, cholesterol supplementation promotes myelin membrane growth. Here, we show that in contrast to the mouse model, dietary cholesterol in two PMD patients did not lead to a major advancement of hypomyelination, potentially because the intact blood-brain barrier precludes its entry into the CNS.

Blood-brain barrier hyperpermeability precedes demyelination in the cuprizone model.

In neuroinflammatory disorders such as multiple sclerosis, the physiological function of the blood-brain barrier (BBB) is perturbed, particularly in demyelinating lesions and supposedly secondary to acute demyelinating pathology. Using the toxic non-inflammatory cuprizone model of demyelination, we demonstrate, however, that the onset of persistent BBB impairment precedes demyelination. In addition to a direct effect of cuprizone on endothelial cells, a plethora of inflammatory mediators, which are mainly of astroglial origin during the initial disease phase, likely contribute to the destabilization of endothelial barrier function in vivo.

Psychosocial factors and quality of life in children and adolescents with implantable cardioverter-defibrillators.

Few data exist on the quality of life in children and adolescents with implantable cardioverter-defibrillators (ICDs). The objective of this study was to determine whether anxiety, depression, family functioning, and quality of life are related to cardiac illness severity in pediatric patients with ICDs. The subjects were 20 patients (mean age 14.

Observational assessment of family functioning at mealtime in preschool children with cystic fibrosis.

Objective: To examine functioning during a dinner meal in families of a child with a chronic illness that requires dietary treatment recommendations, as compared to families of a child without a chronic illness.

Methods: Ratings of seven dimensions of family functioning on the McMaster Mealtime Family Interaction Coding System (MICS) were obtained on 29 families of children with CF and 29 families of children with no chronic illness, ages 2 to 6 years, during a videotaped dinner meal at home.

Results: Ratings of families with a child with CF were significantly lower than those for families of children without a chronic illness on Overall Family Functioning and five of the six MICS dimensions: Communication, Interpersonal Involvement, Affect Management, Behavior Control, and Role Allocation and approached significance on the Task Accomplishment dimension.

A low-glycemic index diet in the treatment of pediatric obesity.

Context: Conventional dietary approaches for the treatment of obesity have generally yielded disappointing results.

Objective: To examine the effects of a low-glycemic index (GI) diet compared with a standard reduced-fat diet in the management of pediatric obesity.

Design: Retrospective cohort study of children attending an outpatient pediatric obesity program from September 1997 to December 1998.

The pediatric psychologist's role in differential diagnosis: vocal-cord dysfunction presenting as asthma.

Presented the case of an 11-year-old boy with vocal-cord dysfunction (VCD) as an example of a rare clinical phenomenon that may result in clinical and systemic challenges for the pediatric psychologist. VCD presents as highly similar to asthma, yet is best treated with speech therapy and psychosocial intervention. The physical symptomatology of VCD and its conceptualization as a psychosomatic disorder are described.

The influence of case and professional variables on identification and reporting of physical abuse: a study with medical students.

Identification and reporting of suspected cases of maltreatment are important precursors to intervention, as maltreating parents typically do not self-refer for treatment. Professionals from various disciplines are legally mandated to report suspected cases of child maltreatment, yet incidences of abuse can remain unidentified or unreported. Identification of physical abuse often depends on careful consideration of the characteristics of the injuries and the plausibility of the explanations provided for the injuries.

Assessment of health-related quality of life in children and adolescents: an integrative review.

Reviewed and integrated the medical and psychological literature on the assessment of health-related quality of life (QOL) in pediatric populations. Definitions of QOL and the utility, health status, battery, and modular approaches to QOL assessment are presented. Measures currently available for use with children and adolescents were evaluated with respect to psychometric properties, QOL domains included, targeted age range, mode of administration, number of items, and time period assessed.

Quality of life assessment in pediatric oncology: a retrospective review of phase III reports.

Background: although the quality of life of cancer patients has been a topic of increasing interest, the research literature to date has generally noted minimal reporting of these data in adult clinical trials.

Purpose: the purpose of this investigation was to examine the frequency with which these measures are reported in pediatric cancer clinical trials.

Method: published reports of 70 Phase III clinical trials from the Pediatric Oncology Group and Childrens Cancer Group were reviewed for presentation of quality of life and toxicity data.