Accumulation of amyloid-␤ (A␤) is one of the earliest molecular events in Alzheimer disease (AD), whereas tau pathology is thought to be a later downstream event. It is now well established that A␤ exists as monomers, oligomers, and fibrils. To study the temporal profile of A␤ oligomer formation in vivo and to determine their interaction with tau pathology, we used the 3xTg-AD mice, which develop a progressive accumulation of plaques and tangles and cognitive impairments. We show that SDS-resistant A␤ oligomers accumulate in an age-dependent fashion, and we present evidence to show that oligomerization of A␤ appears to first occur intraneuronally. Finally, we show that a single intrahippocampal injection of a specific oligomeric antibody is sufficient to clear A␤ pathology, and more importantly, tau pathology. Therefore, A␤ oligomers may play a role in the induction of tau pathology, making the interference of A␤ oligomerization a valid therapeutic target. Alzheimer disease (AD)2 is the most common neurodegenerative disorder, affecting ϳ5 million Americans (1). Neuropathologically, it is characterized by the accumulation of extracellular plaques, mainly comprised of a small peptide called amyloid-␤ (A␤), and intracellular neurofibrillary tangles, consisting of aggregates of hyperphosphorylated tau protein (2). Based on compelling genetic evidence, it has been postulated that pathological assemblies of A␤ are the cause of all forms of AD (3), whereas tau pathology and other neuropathological changes are a downstream consequence of the pathological accumulation of A␤ species. This hypothesis has received strong experimental support from studies of various transgenic models of AD (4 -6). The source of A␤ that initiates the neurodegenerative process, however, remains unknown. Traditionally, A␤ has been viewed as being generated and secreted extracellularly, but it is also becoming increasingly apparent that some A␤ can be generated in different intracellular compartments, such as the endoplasmic reticulum and the trans-Golgi (7-11). Moreover, there is mounting evidence to support a pathophysiologic role for intracellular A␤ in AD an Down syndrome (see Ref. 12 for review).A␤ exists in several different physical states, including as monomers, oligomers, or fibrils. Evidence from in vitro studies demonstrates that synthetic A␤ monomers aggregate in a time-dependent fashion to form oligomers, which eventually may form fibrils (13-15). During the last decade, in vitro and in vivo experimental evidence points to soluble A␤ oligomers, also referred to as A␤-derived diffusible ligands, as the predominant neurotoxic species for neurons (16,17). In this regard, A␤ oligomers are very potent toxic species, as even nanomolar concentrations have been shown to kill mature neurons in hippocampal slices (18). Moreover, A␤ oligomers appear to interfere with many critical neuronal activities, including inhibiting long term potentiation (LTP) in organotypic hippocampal slices (18,19). A␤ oligomers can also cause calcium dysregulation a...

The association between nicotinic acetylcholine receptor (nAChR) dysfunction and cognitive decline in Alzheimer's disease (AD) has been widely exploited for its therapeutic potential. The effects of chronic nicotine exposure on A␤ accumulation have been studied in both humans and animal models, but its therapeutic efficacy for AD neuropathology is still unresolved. To date, no in vivo studies have addressed the consequences of activating nAChRs on tau pathology. To determine the effects of chronic nicotine administration on A␤ and tau pathology, we chronically administrated nicotine to a transgenic model of AD (3xTg-AD) in their drinking water. Here, we show that chronic nicotine intake causes an up-regulation of nicotinic receptors, which correlated with a marked increase in the aggregation and phosphorylation state of tau. These data show that nicotine exacerbates tau pathology in vivo. The increase in tau phosphorylation appears to be due to the activation of p38-mitogen-activated protein kinase, which is known to phosphorylate tau in vivo and in vitro. We also show that the 3xTg-AD mice have an age-dependent reduction of ␣7nAChRs compared with age-matched nontransgenic mice in specific brain regions. The reduction of ␣7nAChRs is first apparent at 6 months of age and is restricted to brain regions that show intraneuronal A␤42 accumulation. Finally, this study highlights the importance of testing compounds designed to ameliorate AD pathology in a model with both neuropathological lesions because of the differential effects it can have on either A␤ or tau.T he loss of cholinergic neurons is a critical event in the pathogenesis of Alzheimer's disease (AD) (1, 2). Acetylcholine (ACh) is a key neuromodulator in the synaptic mechanisms involved with learning and memory (3) and acts through two major receptor subtypes: nicotinic acetylcholine receptors (nAChRs) and muscarinic acetylcholine receptors (mAChRs). Whereas mAChRs are metabotropic, nAChRs are ligand-gated ion channels formed by a combination of five subunits (␣, ␤, ␥, ␦, and ), each encoded by a member of a gene superfamily (4). The ␣7 and ␣4␤2 are two of the major nicotinic receptors subtypes present in the brain (4, 5). For the past several years, a mainstay of AD therapy has been aimed at inhibiting acetylcholinesterase, the enzyme responsible for degrading ACh in the synaptic cleft, and thereby increasing ACh levels in the brain (6). These compounds slow the phenotypical memory impairments; however, their effectiveness is diminished over time.The AD brain is characterized by two pathological hallmarks: amyloid plaques, which are mainly composed of the A␤ peptide, and neurofibrillary tangles (NFTs), which consist of hyperphosphorylated tau protein. Several studies have shown that nAChRs are selectively reduced in the AD brain, particularly in regions harboring plaques and neurofibrillary tangles, suggesting a potential relationship between nicotinic receptors and AD neuropathology (5, 7-9). Notably, chronic nicotine treatment has also been shown to redu...

An abnormal increase in intestinal paracellular permeability may be an important pathogenic factor in various intestinal diseases. The intracellular factors and processes that regulate and cause alteration of intestinal paracellular permeability are not well understood. The purpose of this study was to examine some of the intracellular processes involved in cytoskeletal regulation of intestinal epithelial paracellular permeability using the filter-grown Caco-2 intestinal epithelial monolayers. Cytochalasin-b and colchicine were used to disrupt the cytoskeletal elements, actin microfilaments, and microtubules. Cytochalasin-b (5 micrograms/ml) and colchicine (2 x 10(-5) M) at the doses used caused marked depolymerization and disruption of actin microfilaments and microtubules, respectively. Cytochalasin-b-induced disruption of actin microfilaments resulted in perturbation of tight junctions and desmosomes and an increase in Caco-2 monolayer paracellular permeability. The cytochalasin-b-induced disruption of actin microfilaments and subsequent changes in intercellular junctional complexes and paracellular permeability were not affected by inhibitors of protein synthesis (actinomycin-D or cycloheximide) or microtubule function (colchicine), but were inhibited by metabolic energy inhibitors (2,4-dinitrophenol or sodium azide). The cytochalasin-b-induced disturbance in Caco-2 actin microfilaments and intercellular junctional complexes and increase in paracellular permeability were rapidly reversed. The paracellular pathway "re-tightening" following cytochalasin-b removal was not affected by actinomycin-D, cycloheximide, or colchicine, but was inhibited by 2,4-dinitrophenol and sodium azide. The colchicine-induced disruption of microtubules did not have significant effect on actin microfilaments, intercellular junctions, or paracellular permeability. These findings suggest that cytochalasin-b-induced increase in Caco-2 monolayer paracellular permeability was due to actin microfilament mediated perturbation of intercellular junctional complexes. The re-tightening of paracellular pathways (following removal of cytochalasin-b) resulted from energy-mediated re-assembly of pre-existing actin microfilaments and intercellular junctional complexes. This re-closure process did not require protein synthesis or microtubule-mediated shuttling process.

We investigated the role of morph-based differences in the expression of inbreeding depression in loss of the mid-styled morph from populations of tristylous Oxalis alpina. The extent of self-compatibility (SC) of reproductive morphs, the degree of self-fertilization, and the magnitude of inbreeding depression were investigated in three populations of O. alpina differing in their tristylous incompatibility relationships. All three populations exhibited significant inbreeding depression. In two populations with highly modified tristylous incompatibility, manifested as increased reciprocal compatibility between short- and long-styled morphs, substantial SC and self-fertilization of mid-styled morphs were detected, and expected to result in expression of inbreeding depression in the progeny of mid-styled morphs in the natural populations. In contrast, significant self-fertility of the mid-styled morph was absent from the population with typical tristylous incompatibility, and no self-fertilization could be detected. Although self-fertilization and expression of inbreeding depression should result in selection against the mid-styled morph in the later stages of the transition from tristyly to distyly, in O. alpina selection against the mid-styled morph in the early phases of the evolution of distyly is likely due to genic selection against mid-alleles associated with modified tristylous incompatibility, rather than expression of inbreeding depression.

Inertial Measurement Units (IMUs)-based gait analysis is a promising and attractive approach for user recognition. Recently, the adoption of deep learning techniques has gained significant performance improvement. However, most existing studies focused on exploiting the spatial information of gait data (using Convolutional Neural Network (CNN)) while the temporal part received little attention. In this study, we propose a new multi-model Long Short-term Memory (LSTM) network for learning the gait temporal features. First, we observe that LSTM is able to capture the pattern hidden inside the gait data sequences that are out-of-synchronization. Thus, instead of using the gait cycle-based segment, our model accepts the gait cycle-free segment (i.e., fixed-length window) as the input. By this, the classification task does not depend on the gait cycle detection task, which usually suffers from noise and bias. Second, we propose a new LSTM network architecture, in which, one LSTM is used for each gait data channel and a group of consecutive signals is processed in each step. This strategy allows the network to effectively handle the long input data sequence and achieve improved performance compared to existing LSTM-based gait models. In addition, besides using the LSTM alone, we extend it by combining with a CNN model to construct a hybrid network, which further improves the recognition performance. We evaluated our LSTM and hybrid networks under different settings using the whuGAIT and OU-ISIR datasets. The experiments showed that our LSTM network outperformed the existing LSTM networks, and its combination with CNN established new state-of-the-art performance on both the verification and identification tasks.