ABSTRACT
At diagnosis, Alzheimer's disease (AD) brains are extensively burdened with plaques and tangles and display a degree of synaptic failure most likely beyond therapeutic treatment. It is therefore crucial to identify early pathological events in the progression of the disease. While it is not currently feasible to identify and study early, pre-clinical stages of AD, transgenic (Tg) models offer a valuable tool in this regard. Here we investigated cognitive, structural and biochemical CNS alterations occurring in our newly developed McGill-Thyl-APP Tg mice (over-expressing the human amyloid precursor protein with the Swedish and Indiana mutations) prior to extracellular plaque deposition. Pre-plaque, 3-month old Tg mice already displayed cognitive deficits concomitant with reorganization of cortical cholinergic pre-synaptic terminals. Conformational specific antibodies revealed the early appearance of intracellular amyloid ß (Aß)-oligomers and fibrillar oligomers in pyramidal neurons of cerebral cortex and hippocampus. At the same age, the cortical levels of insulin degrading enzyme -a well established Aß-peptidase, were found to be significantly down-regulated. Our results suggest that, in the McGill-Thy1-APP Tg model, functional, structural and biochemical alterations are already present in the CNS at early, pre-plaque stages of the pathology. Accumulation of intraneuronal neurotoxic Aß-oligomers (possibly caused by a failure in the clearance machinery) is likely to be the culprit of such early, pre-plaque pathology. Similar neuronal alterations might occur prior to clinical diagnosis in AD, during a yet undefined 'latent' stage. A better understanding of such pre-clinical AD might yield novel therapeutic targets and or diagnostic tools.
Subject(s)
Alzheimer Disease/drug therapy , Alzheimer Disease/genetics , Disease Models, Animal , Age Factors , Alzheimer Disease/complications , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Analysis of Variance , Animals , Cerebellum/metabolism , Cerebral Cortex/metabolism , Cognition Disorders/etiology , Drug Evaluation, Preclinical , Gene Expression Regulation/genetics , Hippocampus/metabolism , Humans , Maze Learning/physiology , Mice , Mice, Transgenic , Mutation/genetics , Nuclear Receptor Subfamily 4, Group A, Member 2/metabolism , Peptide Fragments/metabolism , Phosphopyruvate Hydratase/metabolism , Recognition, Psychology/physiology , Vesicular Acetylcholine Transport Proteins/metabolismABSTRACT
OBJECTIVE: To determine the distribution of age-at-onset in a large cohort of patients with restless legs syndrome (RLS) and to compare clinical and polysomnographic characteristics of patients with early and late age-at-onset of RLS. METHODS: Two hundred and fifty patients with RLS were studied. Information on age-at-onset, etiology, familial history and symptoms severity of RLS was obtained. Age-at-onset density functions were determined from bootstrap methods and kernel density estimators. RESULTS: Age-at-onset showed a significant bimodal distribution with a large peak occurring at 20 years of age and a smaller peak in the mid-40s. Early- and late-onset RLS could be separated with a cut-off at 36 years of age. Distributions of age-at-onset differed as a function of presence/absence of a familial history and etiology of RLS. Age-at-onset clearly differentiated patients with a primary RLS (early onset) from those with secondary RLS. Finally, early-onset RLS was associated with increased RLS severity with higher indices of periodic leg movements in sleep (PLMS) associated with microarousals and periodic leg movements during wakefulness (PLMW). CONCLUSIONS: Early- and late-onset RLS could be distinguished depending on familial history and etiology of RLS. Our data suggest that different pathological processes are involved in these two groups, the early-onset group being highly genetically determined.
Subject(s)
Nocturnal Myoclonus Syndrome/diagnosis , Restless Legs Syndrome/diagnosis , Severity of Illness Index , Adult , Age Distribution , Age of Onset , Cohort Studies , Female , Humans , Male , Middle Aged , Multivariate Analysis , Nocturnal Myoclonus Syndrome/epidemiology , Polysomnography/methods , Restless Legs Syndrome/epidemiologyABSTRACT
Since the formulation of the concept of "proteomics" in 1995, a plethora of proteomic technologies have been developed in order to study proteomes of tissues, cells and organelles. The powerful new technologies enabled by proteomic approaches have lead to the application of these methods to an exponentially increasing variety of biological questions for highly complex protein mixtures. Continuous technical optimization allows for an ever-increasing sensitivity of proteomic techniques. In this review, a brief overview of currently available proteomic techniques and their applications is given, followed by a more detailed description of advantages and technical challenges of two-dimensional electrophoresis (2-DE). Some solutions to circumvent currently encountered technical difficulties for 2-DE analyses are proposed.
