alzhiemer's
16399047
Tonic inhibition in dentate gyrus impairs long term potentiation and memory in an Alzhiemer's disease model
SUMMARY Amyloid plaques and tau tangles are common pathological hallmarks for Alzheimer's disease (AD) however reducing Ab production failed to relieve the symptoms of AD patients. Here we report a high GABA (g aminobutyric acid) content in reactive astrocytes in the dentate gyrus (DG) of a mouse model for AD (5xFAD) that results in increased tonic inhibition and memory deficit. We also confirm in human AD patient brains that dentate astrocytes have a high GABA content, suggesting that high astrocytic GABA level may be a novel biomarker and a potential diagnostic tool for AD. The excessive GABA in 5xFAD astrocytes is released through an astrocyte specific GABA transporter GAT3/4, and significantly enhanced tonic GABA inhibition in dentate granule cells. Importantly, reducing tonic inhibition in 5xFAD mice rescues the impairment of long term potentiation (LTP) and memory deficit. Thus, reducing tonic GABA inhibition in the DG may lead to a novel therapy for Alzheimer's disease.
Nature communications
Zheng Da Wu Ziyuan Guo Marla Gearing Gong Chen
3997851
Lack of evidence for dysfunction of the blood brain barrier in Alzhiemer's disease: An immunohistochemical study
With immunohistoperoxidase techniques the presence of plasma (serum) proteins was investigated in senile plaques, congophilic angiopathy, neurons and glial cells in brains of patients with Alzheimer's dementia. Other investigators have found plasma proteins in brain parenchyma and suggested that blood brain barrier dysfunction might be a primary factor in the pathogenesis of Alzheimer's dementia. These studies were performed on formol fixed brains of patients with Alzheimer's dementia. In the present study we investigated both frozen and formol fixed brain tissues. The influence of post mortem delay, prolonged formol fixation and differences in clinical course on detection of plasma proteins by immunocytochemical techniques was also studied. Findings in cases with Alzheimer's dementia were compared with findings in nondemented controls with or without neurological disorders. Plasma proteins could not be demonstrated in the neuropil of a number of patients with Alzheimer's dementia. Moreover, plasma proteins were also found in neuronal cells and astrocytes in brains of nondemented controls. We discussed whether or not cytochemical detection of plasma proteins in the neuropil of post mortem obtained brains is a reliable technique to investigate blood brain barrier dysfunction. In our opinion there are, at the moment, no convincing arguments for blood brain barrier dysfunction in Alzheimer's dementia.
Neurobiology of Aging
J M Rozemuller Piet Eikelenboom Wouter Kamphorst Frank Stam
13700637
Loss of cerebellar glutamate transporters EAAT4 and GLAST differentially affects the spontaneous firing pattern and survival of Purkinje cells
Abstract Loss of excitatory amino acid transporters (EAATs) has been implicated in a number of human diseases including spinocerebellar ataxias, Alzhiemer's disease and motor neuron disease. EAAT4 and GLAST/EAAT1 are the two predominant EAATs responsible for maintaining low extracellular glutamate levels and preventing neurotoxicity in the cerebellum, the brain region essential for motor control. Here using genetically modified mice we identify new critical roles for EAAT4 and GLAST/EAAT1 as modulators of Purkinje cell (PC) spontaneous firing patterns. We show high EAAT4 levels, by limiting mGluR1 signalling, are essential in constraining inherently heterogeneous firing of zebrin positive PCs. Moreover mGluR1 antagonists were found to restore regular spontaneous PC activity and motor behaviour in EAAT4 knockout mice. In contrast, GLAST/EAAT1 expression is required to sustain normal spontaneous simple spike activity in low EAAT4 expressing (zebrin negative) PCs by restricting NMDA receptor activation. Blockade of NMDA receptor activity restores spontaneous activity in zebrin negative PCs of GLAST knockout mice and furthermore alleviates motor deficits. In addition both transporters have differential effects on PC survival, with zebrin negative PCs more vulnerable to loss of GLAST/EAAT1 and zebrin positive PCs more vulnerable to loss of EAAT4. These findings reveal that glutamate transporter dysfunction through elevated extracellular glutamate and the aberrant activation of extrasynaptic receptors can disrupt cerebellar output by altering spontaneous PC firing. This expands our understanding of disease mechanisms in cerebellar ataxias and establishes EAATs as targets for restoring homeostasis in a variety of neurological diseases where altered cerebellar output is now thought to play a key role in pathogenesis.
Human molecular genetics
Emma M Perkins Yvonne L Clarkson Daumante Suminaite Alastair Robert Lyndon Kohichi Tanaka Jeffrey D Rothstein Paul A Skehel David J A Wyllie Mandy Jackson
11117322
Microglial phagocytosis induced by fibrillar b amyloid is attenuated by oligomeric b amyloid: implications for Alzheimer's disease
BackgroundReactive microglia are associated with b amyloid (Ab) deposit and clearance in Alzhiemer's Disease (AD) Paradoxically, entocranial resident microglia fail to trigger an effective phagocytic response to clear Ab deposits although they mainly exist in an "activated" state. Oligomeric Ab (oAb) a recent target in the pathogenesis of AD, can induce more potent neurotoxicity when compared with fibrillar Ab (fAb) However, the role of the different Ab forms in microglial phagocytosis, induction of inflammation and oxidation, and subsequent regulation of phagocytic receptor system, remain unclear.ResultsWe demonstrated that Ab(1 42) fibrils, not Ab(1 42) oligomers, increased the microglial phagocytosis. Intriguingly, the pretreatment of microglia with oAb(1 42) not only attenuated fAb(1 42) triggered classical phagocytic response to fluorescent microspheres but also significantly inhibited phagocytosis of fluorescent labeled fAb(1 42) Compared with the fAb(1 42) treatment, the oAb(1 42) treatment resulted in a rapid and transient increase in interleukin 1b (IL 1b) level and produced higher levels of tumor necrosis factor a (TNF a) nitric oxide (NO) prostaglandin E2 (PGE2) and intracellular superoxide anion (SOA) The further results demonstrated that microglial phagocytosis was negatively correlated with inflammatory mediators in this process and that the capacity of phagocytosis in fAb(1 42) induced microglia was decreased by IL 1b, lippolysaccharide (LPS) and tert butyl hydroperoxide (t BHP) The decreased phagocytosis could be relieved by pyrrolidone dithiocarbamate (PDTC) a nuclear factor kB (NF kB) inhibitor, and N acetyl L cysteine (NAC) a free radical scavenger. These results suggest that the oAb impaired phagocytosis is mediated through inflammation and oxidative stress mediated mechanism in microglial cells. Furthermore, oAb(1 42) stimulation reduced the mRNA expression of CD36, integrin b1 (Itgb1) and Ig receptor FcgRIII, and significantly increased that of formyl peptide receptor 2 (FPR2) and scavenger receptor class B1 (SRB1) compared with the basal level. Interestingly, the pre stimulation with oAb(1 42) or the inflammatory and oxidative milieu (IL 1b, LPS or t BHP) significantly downregulated the fAb(1 42) induced mRNA over expression of CD36, CD47 and Itgb1 receptors in microglial cells.ConclusionThese results imply that Ab oligomers induce a potent inflammatory response and subsequently disturb microglial phagocytosis and clearance of Ab fibrils, thereby contributing to an initial neurodegenerative characteristic of AD. Antiinflammatory and antioxidative therapies may indeed prove beneficial to delay the progression of AD.
Molecular Neurodegeneration
Xiao-Dong Pan Yuan-gui Zhu Nan Lin Jing Zhang Qinqin Ye Huapin Huang Xiao-chun Chen
24945451
Nanoparticles in the treatment and diagnosis of neurological disorders: untamed dragon with fire power to heal.
UNLABELLED The incidence of neurological diseases of unknown etiology is increasing, including well studied diseases such as Alzhiemer's, Parkinson's, and multiple sclerosis. The blood brain barrier provides protection for the brain but also hinders the treatment and diagnosis of these neurological diseases, because the drugs must cross the blood brain barrier to reach the lesions. Thus, attention has turned to developing novel and effective delivery systems that are capable of carrying drug and that provide good bioavailability in the brain. Nanoneurotechnology, particularly application of nanoparticles in drug delivery, has provided promising answers to some of these issues in recent years. Here we review the recent advances in the understanding of several common forms of neurological diseases and particularly the applications of nanoparticles to treat and diagnose them. In addition, we discuss the integration of bioinformatics and modern genomic approaches in the development of nanoparticles. FROM THE CLINICAL EDITOR In this review paper, applications of nanotechnology based diagnostic methods and therapeutic modalities are discussed addressing a variety of neurological disorders, with special attention to blood brain barrier delivery methods. These novel nanomedicine approaches are expected to revolutionize several aspects of clinical neurology.
Nanomedicine nanotechnology, biology, and medicine
Jagat R Kanwar Xueying Sun Vasu Punj Bhasker Sriramoju Rajiv R Mohan Shu-Feng Zhou Ashok Kumar Chauhan Rupinder Kaur Kanwar
25671189
Mn(II) based T1 and T2 potential MRI contrast agent appended with tryptamine: Recognition moiety for Ab plaques.
We report the synthesis and characterization of manganese(II) complexes having pentadentate ligands L1 (2,6 bis(1 (2 phenyl 2 (pyridin 2 yl)hydrazono)ethyl)pyridine) L2 (methyl 2,6 bis((E) 1 (2 phenyl 2 (pyridin 2yl)hydrazono)ethyl)isonicotinate) L3 (N (2 (1H indol 3 yl)ethyl) 2,6 bis((E) 1 (2 phenyl 2 (pyridin2yl)hydrazono)ethyl)isonicotiamide) and their application as dual contrast agents for simultaneous T1 and T2 weighted magnetic resonance imaging. Single crystal analysis of all the complexes [MnIIL1, MnIIL2 and MnIIL3] confirm the formation of novel seven coordinate manganese complexes with an inner sphere water and perchlorate ion. The Magnetic Resonance Imaging (MRI) contrast agent [MnL2] was further modified by incorporating tryptamine as a binding moiety specific to Amyloid Beta fibrils (Ab fibrils) in Alzhiemer's disease (AD) and it's in vitro evaluation for specific binding with Ab fibrils indicated as a bio marker of AD.
Journal of inorganic biochemistry
Neeraj Rastogi Nidhi Tyagi Ovender Singh B S Hemanth Kumar Udai P Singh Kaushik Ghosh Raja Roy
19032730
Molecular and Cellular Mechanism of Okadaic Acid (OKA) Induced Neurotoxicity: A Novel Tool for Alzheimer's Disease Therapeutic Application
Okadaic acid (OKA) a polyether C38 fatty acid toxin extracted from a black sponge Hallichondria okadaii, is a potent and selective inhibitor of protein phosphatase, PP1 and PP2A. OKA has been proved to be a powerful probe for studying the various regulatory mechanisms and neurotoxicity. Because of its property to inhibit phosphatase activity, OKA is associated with protein phosphorylation; it is implicated in hyperphosphorylation of tau and in later stages causes Alzhiemer's disease (AD) like pathology. AD is a progressive neurodegenerative disorder, pathologically characterized by extracellular amyloid beta (Ab) plaques and intracellular neurofibrillary tangles (NFTs) The density of tau tangles in AD pathology is associated with cognitive dysfunction. Recent studies have highlighted the importance of serine/threonine protein phosphatases in many processes including apoptosis and neurotoxicity. Although OKA causes neurotoxicity by various pathways, the exact mechanism is still not clear. The activation of major kinases, such as Ser/Thr, MAPK, ERK, PKA, JNK, PKC, CaMKII, Calpain, and GSK3b, in neurons is associated with AD pathology. These kinases, associated with abnormal hyperphosphorylation of tau, suggest that the cascade of these kinases could exclusively be involved in the pathogenesis of AD. The activity of serine/threonine protein phosphatases needs extensive study as these enzymes are potential targets for novel therapeutics with applications in many diseases including cancer, inflammatory diseases, and neurodegeneration. There is a need to pay ample attention on MAPK kinase pathways in AD, and OKA can be a better tool to study cellular and molecular mechanism for AD pathology. This review elucidates the regulatory mechanism of PP2A and MAPK kinase and their possible mechanisms involved in OKA induced apoptosis, neurotoxicity, and AD like pathology.
Molecular Neurobiology
Pradip Kumar Kamat Shivika Rai Supriya Swarnkar Rakesh Kumar Shukla Chandishwar Nath
11624928
Differential distribution of neurofibrillary tangles in the cerebral cortex of dementia pugilistica and Alzheimer's disease cases
SummaryHead trauma has been associated with the occurrence of Alzhiemer's disease and plays a clear role in the etiopathogenesis of the boxers encephalopathy referred to as dementia pugilistica. Neurofibrillary tangles (NFT) one of the pathological hallmarks of Alzheimer's disease are observed in very high densities in the brains of former professional boxers suffering from dementia pugilistica. In Alzheimer's disease, NFT display striking regional and laminar distribution patterns that have been correlated with the localization of neurons forming specific corticocortical connections. In dementia pugilistica cases, NFT were concentrated in the superficial layers in the neocortex, whereas in Alzheimer's disease they predominated in the deep layers. Thus, the association cortex of brains from dementia pugilistica patients demonstrated an inverse NFT distribution as compared to Alzheimer's disease. This finding suggests that a more circumscribed population of cortical pyramidal neurons might be affected in dementia pugilistica than in Alzheimer's disease.
Acta Neuropathologica
Patrick R Hof Constantin Bouras Luc Buee Andre Delacourte Daniel P Perl John H Morrison
15933227
Rivastigmine transdermal system for the treatment of mild to moderate Alzheimer's disease
Today patients with mild to moderate Alzhiemer's disease (AD) have a treatment approach choice: oral or transdermal delivery. The aim of this review was to provide a concise, comprehensive overview of the clinically relevant safety, tolerability and efficacy information available for the rivastigmine transdermal system. Relevant articles were identified through a MEDLINE search of publications in the past 3 years using the terms 'rivastigmine' and 'transdermal' or 'patch' Efficacy, safety and tolerability of the rivastigmine patch vs. placebo were established in a large, international, 24 week, double blind, randomised clinical trial and subsequent 28 week open label extension study. Drug exposure with the 9.5 mg/24 h rivastigmine patch was not significantly different to that provided by an oral capsule dose of 12 mg/day. Most frequently observed adverse events were gastrointestinal. In the primary study, incidences of nausea, vomiting and diarrhoea were: 5% 3% and 3% respectively in the placebo group; 7% 6% and 6% in the 9.5 mg/24 h rivastigmine patch group; and 23% 17% and 5% in the 12 mg/day capsule group. Most patients experienced no, slight or mild application site skin reactions. De novo patients or those taking oral rivastigmine or donepezil may tolerate a switch to rivastigmine patch. By providing drug exposure that is not significantly different to the highest recommended rivastigmine capsule dose (12 mg/day) with less fluctuation over 24 h, rivastigmine patch offers similar efficacy with an improved tolerability profile. The rivastigmine patch provides a viable treatment option for patients with mild to moderate AD.
International journal of clinical practice
George T Grossberg Carl H Sadowsky Jason T Olin
144610345
Alzheimer's Disease Victims: The "Unbecoming" of Self and the Normalization of Competence
This study examines the importance of routinized practices for the self Alzheimer's disease victims are observed in their daily lives. The deterioration of self is discussed, followed by a discussion of routinized actions and normalization practices by caregivers that allow the patients to be seen as competent selves. Finally, the last remnants of the self in Alzhiemer's patients are discussed. The authors conclude that when the individual self undergoes an "unbecoming" process, due to the mental deterioration caused by the disease, it is largely social practices that allow the self to continue to exist in the eyes of others.
Andrea Fontana Ronald W Smith