Link between DYRK1A overexpression and several-fold enhancement of neurofibrillary degeneration with 3-repeat tau protein in Down syndrome.

Triplication of chromosome 21 in Down syndrome (DS) results in overexpression of the minibrain kinase/dual-specificity tyrosine phosphorylated and regulated kinase 1A gene (DYRK1A). DYRK1A phosphorylates cytoplasmic tau protein and appears in intraneuronal neurofibrillary tangles (NFTs). We have previously shown significantly more DYRK1A-positive NFTs in DS brains than in sporadic Alzheimer disease (AD) brains.

Neurotrophic peptides incorporating adamantane improve learning and memory, promote neurogenesis and synaptic plasticity in mice.

Development of neurotrophic peptidergic drugs that can mimic neurotrophins and promote neurogenesis and maturation of newborn cells into mature functional neurons represents an exciting therapeutic opportunity for treatment of Alzheimer disease and other learning and memory disorders as well as enhancing cognition of normal individuals. Here we report the design of a peptidergic compound, Ac-DGGLAG-NH2, called P21, when administered peripherally, enhanced learning as well as both short-term and spatial reference memories of normal adult C57Bl6 mice. P21 induced enhancement of neurogenesis and maturation of newly born neurons in the granular cell layer and subgranular zone of the dentate gyrus.

Placement, relocation and end of life issues in aging adults with and without Down's syndrome: a retrospective study.

Background: Aging adults with Down's syndrome (DS) experience more relocations and other life events than adults with intellectual disabilities aged 50 and older without DS. Age-related functional decline and the higher incidence of dementia were implicated as the contributing factors that led to relocation and nursing home placement.

Method: A retrospective study of adults with intellectual disabilities who were born prior to the year 1946 was conducted to analyse the number of relocations experienced over a 5- and 10-year period.

Autism severity is associated with child and maternal MAOA genotypes.

Autism severity is associated with child and maternal MAOA genotypes. We replicated and extended a previously reported association between autism severity and a functional polymorphism in the monoamine oxidase A (MAOA) promoter region, MAOA-uVNTR, in a sample of 119 males, aged 2-13 years, with autism spectrum disorder from simplex families. We demonstrated that (i) boys with the low activity 3-repeat MAOA allele had more severe sensory behaviors, arousal regulation problems, and aggression, and worse social communication skills than males with the high activity allele; and (ii) problems with aggression, as well as with fears and rituals, were modified by the mothers' genotype.

Effect of thalidomide on nitric oxide production in lipopolysaccharide-activated RAW 264.7 cells.

Thalidomide is anti-inflammatory under some conditions, yet has been reported to up-regulate Th1 (T helper 1) immunity measured by increased IL-2 (Interleukin-2) and gamma interferon. The authors have assessed the effect of thalidomide and analogues, di- and tri-thiothalidomide, on a lipopolysaccharide (LPS) activated macrophage cell line (RAW 246.7 cells).

The neuropathology of autism: defects of neurogenesis and neuronal migration, and dysplastic changes.

Autism is characterized by a broad spectrum of clinical manifestations including qualitative impairments in social interactions and communication, and repetitive and stereotyped patterns of behavior. Abnormal acceleration of brain growth in early childhood, signs of slower growth of neurons, and minicolumn developmental abnormalities suggest multiregional alterations. The aim of this study was to detect the patterns of focal qualitative developmental defects and to identify brain regions that are prone to developmental alterations in autism.

Increased activities of Na+/K+-ATPase and Ca2+/Mg2+-ATPase in the frontal cortex and cerebellum of autistic individuals.

Aims: Na(+)/K(+)-ATPase and Ca(2+)/Mg(2+)-ATPase are enzymes known to maintain intracellular gradients of ions that are essential for signal transduction. The aim of this study was to compare the activities of Na(+)/K(+)-ATPase and Ca(2+)/Mg(2+)-ATPase in postmortem brain samples from the cerebellum and frontal, temporal, parietal, and occipital cortices from autistic and age-matched control subjects.

Main Methods: The frozen postmortem tissues from different brain regions of autistic and control subjects were homogenized.

Sera from children with autism alter proliferation of human neuronal progenitor cells exposed to oxidation.

Altered brain development during embryogenesis and early postnatal life has been hypothesized to be responsible for the abnormal behaviors of people with autism. The specific genetic background that alters vulnerability to some environmental insults has been suggested in the etiology of autism; however, the specific pathomechanisms have not been identified. Recently, we showed that sera from children with autism alter the maturation of human neuronal progenitor cells (NPCs) in culture.

Comments on 'Significance of developmental expression of amphioxus Branchiostoma belcheri and zebrafish Danio rerio Hsd17b10 in biological and medical research'.

The reported data on the developmental expression of Hsd17b10 gene in Danio rerio is crucial to the utilization of the D. rerio embryo as an animal model for human developmental disorders caused either by mutations on HSD17B10 (formerly HADH2) or by defective expression of the gene. Related diseases were summarized, and it was noticed that hyperinsulinaemic hypoglycaemia is not linked to HSD17B10.

Formation of amyloid-beta oligomers in brain vascular smooth muscle cells transiently exposed to iron-induced oxidative stress.

Vascular smooth muscle cells are involved in deposition of amyloid in brain blood vessels. Accumulation of amyloid-beta peptide (Abeta) in cultured brain vascular smooth muscle cells that overexpress human amyloid-beta precursor protein (APP) Swedish, is strongly enhanced by exposure to iron ions. We studied cellular accumulation of Abeta and APP processing in vascular smooth muscle cells during recovery after exposure to ferrous ions using cells cultured from Tg2576 mice.

The role of overexpressed DYRK1A protein in the early onset of neurofibrillary degeneration in Down syndrome.

The gene encoding the minibrain kinase/dual-specificity tyrosine phosphorylated and regulated kinase 1A (DYRK1A) is located in the Down syndrome (DS) critical region of chromosome 21. The third copy of DYRK1A is believed to contribute to abnormal brain development in patients with DS. In vitro studies showing that DYRK1A phosphorylates tau protein suggest that this kinase is also involved in tau protein phosphorylation in the human brain and contributes to neurofibrillary degeneration, and that this contribution might be enhanced in patients with DS.

Failure of neuronal maturation in Alzheimer disease dentate gyrus.

The dentate gyrus, an important anatomic structure of the hippocampal formation, is one of the major areas in which neurogenesis takes place in the adult mammalian brain. Neurogenesis in the dentate gyrus is thought to play an important role in hippocampus-dependent learning and memory. Neurogenesis has been reported to be increased in the dentate gyrus of patients with Alzheimer disease, but it is not known whether the newly generated neurons differentiate into mature neurons.

Binding of proteases to fibrillar amyloid-beta protein and its inhibition by Congo red.

Fibrillar amyloid-beta protein (fAbeta) is the principal component of amyloid plaques in the brains of patients with Alzheimer's disease (AD). We have recently reported that activity of trypsin is inhibited by fAbeta and that trypsin can bind to fAbeta. Neprilysin and insulysin are important proteases for the clearance of soluble Abeta.

Alzheimer's disease in Down syndrome: neurobiology and risk.

Down syndrome (DS) is characterized by increased mortality rates, both during early and later stages of life, and age-specific mortality risk remains higher in adults with DS compared with the overall population of people with mental retardation and with typically developing populations. Causes of increased mortality rates early in life are primarily due to the increased incidence of congenital heart disease and leukemia, while causes of higher mortality rates later in life may be due to a number of factors, two of which are an increased risk for Alzheimer's disease (AD) and an apparent tendency toward premature aging. In this article, we describe the increase in lifespan for people with DS that has occurred over the past 100 years, as well as advances in the understanding of the occurrence of AD in adults with DS.

Intraneuronal Abeta immunoreactivity is not a predictor of brain amyloidosis-beta or neurofibrillary degeneration.

Amyloid beta (Abeta) immunoreactivity in neurons was examined in brains of 32 control subjects, 31 people with Down syndrome, and 36 patients with sporadic Alzheimer's disease to determine if intraneuronal Abeta immunoreactivity is an early manifestation of Alzheimer-type pathology leading to fibrillar plaque formation and/or neurofibrillary degeneration. The appearance of Abeta immunoreactivity in neurons in infants and stable neuron-type specific Abeta immunoreactivity in a majority of brain structures during late childhood, adulthood, and normal aging does not support this hypothesis. The absence or detection of only traces of reaction with antibodies against 4-13 aa and 8-17 aa of Abeta in neurons indicated that intraneuronal Abeta was mainly a product of alpha- and gamma-secretases (Abeta(17-40/42)).

MNB/DYRK1A phosphorylation regulates the interactions of synaptojanin 1 with endocytic accessory proteins.

MNB/DYRK1A is a proline-directed serine/threonine kinase implicated in Down syndrome (DS). In an earlier screening, two proteins from adult rat brain, one 100kDa and the other 140 kDa, were found to be prominently phosphorylated by the kinase. The 100-kDa protein was previously characterized as an isoform of dynamin 1.

Tripeptidyl-peptidase I in health and disease.

The lysosomal lumen contains numerous acidic hydrolases involved in the degradation of carbohydrates, lipids, proteins, and nucleic acids, which are basic cell components that turn over continuously within the cell and/or are ingested from outside of the cell. Deficiency in almost any of these hydrolases causes accumulation of the undigested material in secondary lysosomes, which manifests itself as a form of lysosomal storage disorder (LSD). Mutations in tripeptidyl-peptidase I (TPP I) underlie the classic late-infantile form of neuronal ceroid lipofuscinoses (CLN2), the most common neurodegenerative disorders of childhood.

Oxidative stress in Alzheimer's disease.

Oxidative damage is a major feature in the pathophysiology of Alzheimer's disease (AD). In this review, we discuss free radical-mediated damage to the biochemical components involved in the pathology and clinical symptoms of AD. We explain how amyloid beta-protein (Abeta), microtubule-associated protein tau, presenilins, apolipoprotein E, mitochondria and proteases play a role in increasing oxidative stress in AD.

Oxidative stress in autism.

Autism is a severe developmental disorder with poorly understood etiology. Oxidative stress in autism has been studied at the membrane level and also by measuring products of lipid peroxidation, detoxifying agents (such as glutathione), and antioxidants involved in the defense system against reactive oxygen species (ROS). Lipid peroxidation markers are elevated in autism, indicating that oxidative stress is increased in this disease.

Binding of trypsin to fibrillar amyloid beta-protein.

We have recently reported that fibrillar amyloid beta-protein (Abeta) inhibits the proteolytic activity of trypsin and high molecular weight bovine brain protease. We report here that trypsin binds to fibrillar Abeta (fAbeta) and the resulting complex of trypsin/fAbeta is sodium dodecyl sulfate (SDS)-stable. Electron microscopic analysis confirmed the binding of trypsin on the fibrils of both Abeta 1-40 and Abeta 1-42.

Metabolic depression in hibernation and major depression: an explanatory theory and an animal model of depression.

Metabolic depression, an adaptive biological process for energy preservation, is responsible for torpor, hibernation and estivation. We propose that a form of metabolic depression, and not mitochondrial dysfunction, is the process underlying the observed hypometabolism, state-dependent neurobiological changes and vegetative symptoms of major depression in humans. The process of metabolic depression is reactivated via differential gene expression in response to perceived adverse stimuli in predisposed persons.

Regulation of high molecular weight bovine brain neutral protease by phospholipids in vitro.

The activity of the heat stable, glycosylated high molecular weight bovine brain neutral protease (HMW protease) is differentially regulated by phospholipids. While phosphatidylcholine (PC), phosphatidylserine (PS) and phosphatidic acid (PA) had only marginal stimulatory effect (40-75%) on the activity of HMW protease, lysophoshatidylcholine (lysoPC) and lysophosphatidic acid (lysoPA) activated the enzyme by more than two-fold. Both lysoPC and lysoPA exhibited concentration-dependent saturation kinetics for the activation of HMW protease.

Walnut extract inhibits the fibrillization of amyloid beta-protein, and also defibrillizes its preformed fibrils.

Fibrillar amyloid beta-protein (Abeta) is the principal component of amyloid plaques in the brains of patients with Alzheimer's disease. We have studied the effect of walnut extract on Abeta fibrillization by Thioflavin T fluorescence spectroscopy and electron microscopy. The walnut extract not only inhibited Abeta fibril formation in a concentration and time- dependent manner but it was also able to defibrillize Abeta preformed fibrils.