Large-Scale Phenotyping of an Accurate Genetic Mouse Model of JNCL Identifies Novel Early Pathology Outside the Central Nervous System

Cln3Δex7/8 mice harbor the most common genetic defect causing juvenile neuronal ceroid lipofuscinosis (JNCL), an autosomal recessive disease involving seizures, visual, motor and cognitive decline, and premature death. Here, to more thoroughly investigate the manifestations of the common JNCL mutation, we performed a broad phenotyping study of Cln3Δex7/8 mice. Homozygous Cln3Δex7/8 mice, congenic on a C57BL/6N background, displayed subtle deficits in sensory and motor tasks at 10–14 weeks of age. Homozygous Cln3Δex7/8 mice also displayed electroretinographic changes reflecting cone function deficits past 5 months of age and a progressive decline of retinal post-receptoral function. Metabolic analysis revealed increases in rectal body temperature and minimum oxygen consumption in 12–13 week old homozygous Cln3Δex7/8mice, which were also seen to a lesser extent in heterozygous Cln3Δex7/8 mice. Heart weight was slightly increased at 20 weeks of age, but no significant differences were observed in cardiac function in young adults. In a comprehensive blood analysis at 15–16 weeks of age, serum ferritin concentrations, mean corpuscular volume of red blood cells (MCV), and reticulocyte counts were reproducibly increased in homozygous Cln3Δex7/8 mice, and male homozygotes had a relative T-cell deficiency, suggesting alterations in hematopoiesis. Finally, consistent with findings in JNCL patients, vacuolated peripheral blood lymphocytes were observed in homozygous Cln3Δex7/8 neonates, and to a greater extent in older animals. Early onset, severe vacuolation in clear cells of the epididymis of male homozygous Cln3Δex7/8 mice was also observed. These data highlight additional organ systems in which to study CLN3 function, and early phenotypes have been established in homozygous Cln3Δex7/8 mice that merit further study for JNCL biomarker development

Disruption of arterial perivascular drainage of amyloid-β from the brains of mice expressing the human APOE ε4 allele

Failure of elimination of amyloid-β (Aβ) from the brain and vasculature appears to be a key factor in the etiology of sporadic Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). In addition to age, possession of an apolipoprotein E (APOE) ε4 allele is a strong risk factor for the development of sporadic AD. The present study tested the hypothesis that possession of the APOE ε4 allele is associated with disruption of perivascular drainage of Aβ from the brain and with changes in cerebrovascular basement membrane protein levels. Targeted replacement (TR) mice expressing the human APOE3 (TRE3) or APOE4 (TRE4) genes and wildtype mice received intracerebral injections of human Aβ40. Aβ40 aggregated in peri-arterial drainage pathways in TRE4 mice, but not in TRE3 or wildtype mice. The number of Aβ deposits was significantly higher in the hippocampi of TRE4 mice than in the TRE3 mice, at both 3- and 16-months of age, suggesting that clearance of Aβ was disrupted in the brains of TRE4 mice. Immunocytochemical and Western blot analysis of vascular basement membrane proteins demonstrated significantly raised levels of collagen IV in 3-month-old TRE4 mice compared with TRE3 and wild type mice. In 16-month-old mice, collagen IV and laminin levels were unchanged between wild type and TRE3 mice, but were lower in TRE4 mice. The results of this study suggest that APOE4 may increase the risk for AD through disruption and impedance of perivascular drainage of soluble Aβ from the brain. This effect may be mediated, in part, by changes in age-related expression of basement membrane proteins in the cerebral vasculature

Heat Shock Proteins and Amateur Chaperones in Amyloid-Beta Accumulation and Clearance in Alzheimer’s Disease

The pathologic lesions of Alzheimer’s disease (AD) are characterized by accumulation of protein aggregates consisting of intracellular or extracellular misfolded proteins. The amyloid-β (Aβ) protein accumulates extracellularly in senile plaques and cerebral amyloid angiopathy, whereas the hyperphosphorylated tau protein accumulates intracellularly as neurofibrillary tangles. “Professional chaperones”, such as the heat shock protein family, have a function in the prevention of protein misfolding and subsequent aggregation. “Amateur” chaperones, such as apolipoproteins and heparan sulfate proteoglycans, bind amyloidogenic proteins and may affect their aggregation process. Professional and amateur chaperones not only colocalize with the pathological lesions of AD, but may also be involved in conformational changes of Aβ, and in the clearance of Aβ from the brain via phagocytosis or active transport across the blood–brain barrier. Thus, both professional and amateur chaperones may be involved in the aggregation, accumulation, persistence, and clearance of Aβ and tau and in other Aβ-associated reactions such as inflammation associated with AD lesions, and may, therefore, serve as potential targets for therapeutic intervention

Neuronal degeneration and reorganization: a mutual principle in pathological and in healthy interactions of limbic and prefrontal circuits.

Teuchert-Noodt G. Neuronal degeneration and reorganization: a mutual principle in pathological and in healthy interactions of limbic and prefrontal circuits. J Neural Transm Suppl. 2000;(60):315-333.Based on developmental principles and insights from animal research about neuroplasticity in cell assemblies, this article is to propose a view of plasticity that promotes a link between hippocampal and prefrontal structure and function. Both the mitotic activity (counting of BrdU-labeled cells) in hippocampal dentatus and the maturation of dopamine fibres (quantitative immunochemistry of mesoprefrontal projection) in the prefrontal cortex proved to be a measurable combination for investigating the complex chain of events that relate activity dependent neuroplasticity to normal as well as to pathological maturational processes. With our animal model we demonstrate that both rearing conditions and neuroactive substances can effectively interfere with developmental plasticity and induce a malfunctional adaptation of prefrontal structures and neurotransmitter systems (dopamine, GABA). In the hippocampal dentatus, where ontogenetic plasticity proved to be preserved by continued neuro- and synaptogenesis, serious damage can be internalized without simultaneous disruption of neural dynamics offering an approach to reverse dysfunctional reorganization in the prefrontal cortex

Sulfation of heparan sulfate associated with amyloid-beta plaques in patients with Alzheimer's disease.

Contains fulltext : 89112.pdf (publisher's version ) (Closed access)Alzheimer's disease (AD) is characterized by pathological lesions such as amyloid-beta (Abeta) plaques and cerebral amyloid angiopathy. Both these lesions consist mainly of aggregated Abeta protein and this aggregation is affected by macromolecules such as heparan sulfate (HS) proteoglycans. Previous studies demonstrated that HS enhances fibrillogenesis of Abeta and that this enhancement is dependent on the degree of sulfation of HS. In addition, it has been reported that these sulfation epitopes do not occur randomly but have a defined tissue distribution. Until now, the distribution of sulfation epitopes of HS has not yet been studied in human brain. We investigated whether a specific HS epitope is associated with Abeta plaques by performing immunohistochemistry on occipital neocortical and hippocampal tissue sections from AD patients using five HS epitope-specific phage display antibodies. Antibodies recognizing highly N-sulfated HS demonstrated the highest level of staining in both fibrillar Abeta plaques and non-fibrillar Abeta plaques, whereas antibodies recognizing HS regions with a lower degree of N-sulfate modifications were only immunoreactive with fibrillar Abeta plaques. Thus, our results suggest that a larger variety of HS epitopes is associated with fibrillar Abeta plaques, but the HS epitopes associated with non-fibrillar Abeta plaques seem to be more restricted, selectively consisting of highly N-sulfated epitopes.1 februari 201

Efeitos do exercício físico sobre o estado redox cerebral Effects of physical exercise over the redox brain state

A atividade física é conhecida por promover saúde e bem-estar. O exercício também é responsável por aumentar a produção de Espécies Reativas de Oxigênio (ERO) pelo acréscimo do consumo de oxigênio mitocondrial nos tecidos. O desequilíbrio entre a produção de EROs e as defesas oxidantes dos tecidos pode provocar danos oxidativos a proteínas, lipídios e DNA. O dano oxidativo cerebral é um mecanismo etiopatológico comum da apoptose e da neurodegeneração. O fator de crescimento cérebro-derivado desempenha um importante papel neste contexto. Nesta revisão, apresentamos os resultados de diferentes modelos de exercício físico no metabolismo oxidativo e neurotrófico do Sistema Nervoso Central (SNC). Também revisamos estudos que utilizaram suplementação antioxidante para prevenir danos oxidativos exercício-induzido ao SNC. Os modelos de exercício físico mais comuns foram as rodas de correr, a natação e a esteira com configurações de treinamento muito diferentes como a duração e a intensidade. Os resultados do treinamento físico no tecido cerebral são muito controversos, mas geralmente demonstram ganhos na plasticidade sináptica e na função cognitiva com exercícios de intensidade moderada e baixa.<br>Physical activity is known for promoting health and well-being. Exercise is also responsible for increasing the production of Oxygen Reactive Species (ORS) by increasing mitochondrial oxygen consumption causing tissue oxidative stress. The imbalance between ORS production and tissue antioxidant defenses can cause oxidative damage to proteins, lipids and DNA. Brain oxidative damage is a common etiopathology mechanism of apoptosis and neurodegeneration. The brain-derived neurotrophic factor plays an important role in this context. In this review, we showed the results of different models and configurations of physical exercise in oxidative and neurotrophic metabolism of the Central Nervous System (CNS). We also reviewed studies that utilized antioxidant supplementation to prevent exercise-induced oxidative damage to CNS. The commonest physical exercise models were running wheels, swimming and treadmill with very different configurations of physical training such as duration and intensity. The results of physical training on brain tissues are very controversial, but generally show improvement in synaptic plasticity and cognition function with low and moderate intensity exercises