1.
Altered CSF Orexin and α-Synuclein Levels in Dementia Patients.
Source
Molecular Memory Research Unit, The Wallenberg Lab, Lund University, Department of Clinical Sciences Malmö, Sweden.
Abstract
Neurodegenerative dementia, most frequently represented by Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), is often accompanied by altered sleeping patterns and excessive daytime sleepiness. Studies showing an association between the neuropeptide orexin and AD/DLB-related processes such as amyloid-β (Aβ)1-42 plaqueformation, α-synuclein accumulation, and inflammation indicate that orexin might play a pathogenic role similar to the situation in narcolepsy. Our study of patients with AD (n = 26), DLB (n = 18), and non-demented controls (n = 24) shows a decrease in cerebrospinal fluid (CSF) orexin concentrations in DLB versus AD patients and controls. The observed differences in orexin levels were found to be specific to female DLB patients. We also show that the female DLB patients exclusively displayed lower levels of α-synuclein compared to AD patients and controls. Orexin was linked to α-synuclein and total-tau in female non-demented controls whereas associations between orexin and Aβ1-42 concentrations were absent in all groups regardless of gender. Thus, the proposed links between orexin, Aβ, and α-synuclein pathology could not be monitored in CSF protein concentrations. Interestingly, α-synuclein was strongly correlated to the CSF levels of total-tau in all groups, suggesting α-synuclein to be an unspecific marker of neurodegeneration. We conclude that lower levels of CSF orexin are specific to DLB versus AD and appear unrelated to Aβ1-42 and α-synuclein levels in AD and DLB. Alterations in CSF orexin and α-synuclein levels may be related to gender which warrants further investigation.
Calpastatin modulates APP processing in the brains of β-amyloid depositing but not wild-type mice.
Source
Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA; New York University School of Medicine, New York, NY, USA.
Abstract
We report that neuronal overexpression of the endogenous inhibitor of calpains, calpastatin (CAST), in a mouse model of human Alzheimer's disease (AD) β-amyloidosis, the APP23 mouse, reduces β-amyloid (Aβ) pathology and Aβ levels when comparing aged, double transgenic (tg) APP23/CAST with APP23 mice. Concurrent with Aβ plaque deposition, aged APP23/CAST mice show a decrease in the steady-state brain levels of the amyloid precursor protein (APP) and APP C-terminal fragments (CTFs) when compared with APP23 mice. This CAST-dependent decrease in APP metabolite levels was not observed in single tg CAST mice expressing endogenous APP or in younger, Aβ plaque predepositing APP23/CAST mice. We also determined that the CAST-mediated inhibition of calpain activity in the brain is greater in the CAST mice with Aβ pathology than in non-APP tg mice, as demonstrated by a decrease in calpain-mediated cytoskeleton protein cleavage. Moreover, aged APP23/CAST mice have reduced extracellular signal-regulated kinase 1/2 (ERK1/2) activity and tau phosphorylation when compared with APP23 mice. In summary, in vivo calpain inhibition mediated by CAST transgene expression reduces Aβ pathology in APP23 mice, with our findings further suggesting that APP metabolism is modified by CAST overexpression as the mice develop Aβ pathology. Our results indicate that the calpain system in neurons is more responsive to CAST inhibition under conditions of Aβ pathology, suggesting that in the disease state neurons may be more sensitive to the therapeutic use of calpain inhibitors.
Copyright © 2011 Elsevier Inc. All rights reserved.
Phosphorus Dendrimers Affect Alzheimer's (Aβ1-28) Peptide and MAP-Tau Protein Aggregation.
Abstract
Alzheimer's disease (AD) is characterized by pathological aggregation of β-amyloid peptides and MAP-Tau protein. β-amyloid (Aβ) is a peptide responsible for extracellular Alzheimer's plaque formation. Intracellular MAP-Tau aggregates appear as a result of hyperphosphorylation of this cytoskeletal protein. Small, oligomeric forms of Aβ are intermediate products that appear before the amyloid plaques are formed. These forms are believed to be most neurotoxic. Dendrimers are highly branched polymers, which may find an application in regulation of amyloid fibril formation. Several biophysical and biochemical methods, like circular dichroism (CD), fluorescence intensity of thioflavin T and thioflavin S, transmission electron microscopy, spectrofluorimetry (measuring quenching of intrinsic peptide fluorescence) and MTT-cytotoxicity assay, were applied to characterize interactions of cationic phosphorus-containing dendrimers of generation 3 and generation 4 (CPDG3, CPDG4) with the fragment of amyloid peptide (Aβ1-28) and MAP-Tau protein. We have demonstrated that CPDs are able to affect β-amyloid and MAP-Tau aggregation processes. A neuro-2a cell line (N2a) was used to test cytotoxicity of formed fibrils and intermediate products during the Aβ1-28 aggregation. It has been shown that CPDs might have a beneficial effect by reducing the system toxicity. Presented results suggest that phosphorus dendrimers may be used in the future as agents regulating the fibrilization processes in Alzheimer's disease.
Brain Serum Amyloid P Levels are Reduced in Individuals that Lack Dementia While Having Alzheimer's Disease Neuropathology.
Source
Department of Biochemistry and Cell Biology, Rice University, Houston, TX, 77005-1894, USA.
Abstract
The neuropathological signs of Alzheimer's disease (AD) include beta amyloid plaques and neurofibrillary tangles. There is a significant population of individuals that have these key hallmarks but show no signs of cognitive impairment, termed non-demented with AD neuropathology (NDAN). The protective mechanism allowing these individuals to escape dementia is unknown. Serum amyloid P (SAP) is a serum protein associated with wound repair that is elevated in the brains of Alzheimer's patients and binds to amyloid plaques. Using immunoblotting and immunohistochemistry, we evaluated SAP levels in postmortem samples of hippocampus and frontal cortex in age-matched controls, AD, and NDAN individuals. AD individuals had significantly increased SAP levels compared to normal controls, while NDAN samples had no significant difference in SAP levels compared to normal controls. Our results suggest that low levels of SAP in plaques marks the brains of individuals that escape dementia despite the presence of beta amyloid plaques and tangles.
Spines, plasticity, and cognition in Alzheimer's model mice.
Source
Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, MA 02129, USA.
Abstract
The pathological hallmarks of Alzheimer's disease (AD)-widespread synaptic and neuronal loss and the pathological accumulation of amyloid-beta peptide (Aβ) in senile plaques, as well as hyperphosphorylated tau in neurofibrillary tangles-have been known for many decades, but the links between AD pathology and dementia and effective therapeutic strategies remain elusive. Transgenic mice have been developed based on rare familial forms of AD and frontotemporal dementia, allowing investigators to test in detail the structural, functional, and behavioral consequences of AD-associated pathology. Here, we review work on transgenic AD models that investigate the degeneration of dendritic spine structure, synaptic function, and cognition. Together, these data support a model of AD pathogenesis in which soluble Aβ initiates synaptic dysfunction and loss, as well as pathological changes in tau, which contribute to both synaptic and neuronal loss. These changes in synapse structure and function as well as frank synapse and neuronal loss contribute to the neural system dysfunction which causes cognitive deficits. Understanding the underpinnings of dementia in AD will be essential to develop and evaluate therapeutic approaches for this widespread and devastating disease.
White Matter Lesions Are Not Related to β-Amyloid Deposition in an Autopsy-Based Study.
Source
Department of Neurology, Donders Centre for Neuroscience, Medical Centre, Radboud University Nijmegen, 6500 HB Nijmegen, The Netherlands.
Abstract
Population-based studies have investigated the relation between β-amyloid levels in cerebrospinal fluid or plasma and white matter lesions (WMLs). However, these circulating levels of β-amyloid in cerebrospinal fluid or plasma may not reliably reflect the actual degree of amyloid present in the brain. Therefore, we investigated the relation between WMLs and β-amyloid plaques and amyloid angiopathy in brain tissue. WML on MRI or CT were rated in 28 nondemented patients whose neuroimaging was available prior to death. β-amyloid in plaques and arterioles were immunohistochemically stained and quantified in postmortem brain necropsies. WMLs were present in 43% of the total population. Both cortex and periventricular region showed no differences for β-amyloid deposition in either plaques or blood vessel walls in patients with WMLs compared to those without WMLs. Thus, our results indicate that there is no relation between the degree of WMLs and β-amyloid deposition in the brain.
The contributions of unscheduled neuronal cell cycle events to the death of neurons in Alzheimer's disease.
Source
Dept. of Cell Biology and Neuroscience, Nelson Biological Laboratories, 604 Allison Road, Piscataway, NJ 0854.
Abstract
Alzheimer's disease is a neurodegenerative disorder that accounts for the majority of the dementia in individuals over the age of 65. While much has been learned about the biology and biochemistry of the tau tangles and beta-amyloid plaques, less is known about the cell biology of the neuronal cell death process. This review examines one feature of this process, the unexpected occurrence of unscheduled cell cycle events in mature and normally non-mitotic neurons in the at-risk neuronal populations. The correlation of neuronal cell cycling and cell death is not unique to Alzheimer's, but the evidence in both human Alzheimer's disease and its mouse models suggests that these events are early disease related processes, that they are driving forces of the disease rather than indirect symptoms. Defining the biochemistry behind cell cycle initiation holds promise as a fresh therapeutic approach in the battle against this devastating disease.
- PMID:
- 22202022
- [PubMed - in process]
Metals in alzheimer's disease: a systemic perspective.
Source
Department of Neuroscience, AFaR, Fatebenefratelli Hospital, Rome, Italy, Department of Neurology, Campus Biomedico, University, Rome, Italy.
Abstract
Many results from in vitro and animal studies have highlighted the important role played by specific metals, such as copper, iron and zinc, in the diverse toxic pathways on which Alzheimer's disease (AD) develops. Metals seem to mediate the aggregation and neurotoxicity of amyloid-beta (ABeta), the main constituent of the amyloid plaques, commonly seen in AD (1). The link between metals and AD has been mostly investigated with a focus on their local accumulation in defined areas of the brain critical for AD. In the present review, I have instead approached the issue from the different perspective of a systemic, rather than local, alteration of copper and iron status. This view is supported by the results of a series of in vivo studies demonstrating that abnormalities of metals homeostasis correlate with the main deficits and specific markers of AD, such as ABeta and Tau proteins in the cerebrospinal fluid. These findings clearly suggest that local metals accumulation in brain areas critical for AD should be viewed within a wider framework of metals systemic alteration.
- PMID:
- 22201755
- [PubMed - in process]
Structural Basis of C-terminal β-Amyloid Peptide Binding by the Antibody Ponezumab for the Treatment of Alzheimer's Disease.
Source
Rinat, Pfizer Inc., 230 East Grand Avenue, South San Francisco, CA 94080, USA.
Abstract
Alzheimer's disease, the most common cause of dementia in the elderly and characterized by the deposition and accumulation of plaques, is composed in part of β-amyloid (Aβ) peptides, loss of neurons, and the accumulation of neurofibrillary tangles. Here, we describe ponezumab, a humanized monoclonal antibody, and show how it binds specifically to the carboxyl (C)-terminus of Aβ40. Ponezumab can label Aβ that is deposited in brain parenchyma found in sections from Alzheimer's disease casualties and in transgenic mouse models that overexpress Aβ. Importantly, ponezumab does not label full-length, non-cleaved amyloid precursor protein on the cell surface. The C-terminal epitope of ponezumab appears to be available for binding soluble Aβ present in the circulation because systemic administration of ponezumab greatly elevates plasma Aβ40 levels in a dose-dependent fashion after administration to a mouse model that overexpress human Aβ. Administration of ponezumab to transgenic mice also led to a dose-dependent reduction in hippocampal amyloid load. To further explore the nature of ponezumab binding to Aβ40, we determined the X-ray crystal structure of ponezumab in complex with Aβ40 and found that the Aβ40 carboxyl moiety makes extensive contacts with ponezumab. Furthermore, the structure-function analysis supported this critical requirement for carboxy group of AβV40 in the Aβ-ponezumab interaction. These findings provide novel structural insights into the in vivo conformation of the C-terminus of Aβ40 and the brain Aβ-lowering efficacy that we observed following administration of ponezumab in transgenic mouse models.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Cognitive phenotyping of amyloid precursor protein transgenic J20 mice.
Source
Neuroscience Research Australia, Randwick, NSW 2031, Australia; Schizophrenia Research Institute, Darlinghurst, NSW 2010, Australia; School of Psychology, University of New South Wales, Sydney, NSW 2052, Australia.
Abstract
Transgenic mice that express familial Alzheimer's disease mutant forms of the human amyloid precursor protein (hAPP) have proved to be invaluable in determining the impact that the neurotoxic amyloid-β peptide has in vivo. In addition to the propensity to accumulate cerebral amyloid plaques, a crucial characteristic of hAPP mouse models, is their cognitive impairments. To date the most widely used test for analyzing cognitive impairment in hAPP mice is the Morris water maze (MWM) which, due to the fact that mice are not "natural" swimmers, may not always be the ideal paradigm to investigate cognitive behaviours. Furthermore, other cognitive impairments have not been replicated across research laboratories. In the current study, we characterised the cognitive abilities of the J20 transgenic mouse line (expressing the Swedish 670/671(KM->NL) and Indiana 717(V->F)hAPP mutations) and non-transgenic mice. Mice were assessed in the cheeseboard task (i.e., a 'dry version' of the MWM) and a variety of other cognitive paradigms to test fear conditioning, object recognition and short-term memory to broaden the understanding of the cognitive deficits in J20 mice. hAPP transgenic mice perform normally in tasks for fear conditioning, short-term object recognition and short-term memory of context familiarity. However, they were profoundly impaired in their spatial reference memory capabilities in the cheeseboard task. The cheeseboard task has potential to replace the MWM task in situations where the MWM is not suitable for particular mouse models.
Copyright © 2011. Published by Elsevier B.V.
Intracranial V. cholerae Sialidase Protects against Excitotoxic Neurodegeneration.
Source
Departments of Neurology and Anatomy & Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
Abstract
Converging evidence shows that GD3 ganglioside is a critical effector in a number of apoptotic pathways, and GM1 ganglioside has neuroprotective and noötropic properties. Targeted deletion of GD3 synthase (GD3S) eliminates GD3 and increases GM1 levels. Primary neurons from GD3S-/- mice are resistant to neurotoxicity induced by amyloid-β or hyperhomocysteinemia, and when GD3S is eliminated in the APP/PSEN1 double-transgenic model of Alzheimer's disease the plaque-associated oxidative stress and inflammatory response are absent. To date, no small-molecule inhibitor of GD3S exists. In the present study we used sialidase from Vibrio cholerae (VCS) to produce a brain ganglioside profile that approximates that of GD3S deletion. VCS hydrolyzes GD1a and complex b-series gangliosides to GM1, and the apoptogenic GD3 is degraded. VCS was infused by osmotic minipump into the dorsal third ventricle in mice over a 4-week period. Sensorimotor behaviors, anxiety, and cognition were unaffected in VCS-treated mice. To determine whether VCS was neuroprotective in vivo, we injected kainic acid on the 25th day of infusion to induce status epilepticus. Kainic acid induced a robust lesion of the CA3 hippocampal subfield in aCSF-treated controls. In contrast, all hippocampal regions in VCS-treated mice were largely intact. VCS did not protect against seizures. These results demonstrate that strategic degradation of complex gangliosides and GD3 can be used to achieve neuroprotection without adversely affecting behavior.
Molecular Imaging of Amyloidosis: Will the Heart Be the Next Target After the Brain?
Source
Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, 22 South Greene Street, Baltimore, MD, 21201, USA, wchen5@umm.edu.
Abstract
Amyloidosis is a heterogeneous group of diseases with a common feature of extracellular deposition and infiltration of different types of amyloid fibrils in various organs. For example, Alzheimer's disease is characterized by deposition ofamyloid β in the brain. Radiolabeled positron emission tomography (PET) tracers, mainly derivatives of thioflavin-T, were recently introduced for identification of amyloid β plaques in Alzheimer's patients. Such advances of amyloid β plaqueimaging of the brain may shed light into imaging of other organs in amyloidosis patients, such as the heart. Cardiac infiltration of amyloid confers poor clinical outcomes, which renders early diagnosis for appropriate clinical management. At present, nuclear imaging of cardiac amyloidosis is predominantly accomplished with bone-seeking radiotracers, such as 99m-technetium-labeled pyrophosphate ((99m)Tc-PYP), 99m-technetium-methylene diphosphonate ((99m)Tc-MDP), and 99m-technetium-3,3,-diphosphono-1,2-propanodicarboxylic acid ((99m)Tc-DPD), with conflicting results in terms of diagnostic performance, with the exception for (99m)Tc-DPD, which may differentiate light-chain amyloidosis from transthyretin-related cardiac amyloidosis. Although other non-bone-seeking radiotracers such as iodine-123-labeledamyloid P component ((123)I-SAP), 123-iodine-Meta-iodobenzylguanidine ((123)I-mIBG), 99m-technetium-labeled protease inhibitor, and indium-111-labeled amyloid antibodies have also shown some success in identifying cardiac amyloidosis, the future, however, may lie in labeling derivatives of thioflavin-T. With the recent success of visualizing deposition of amyloid β in the brain, the US Food and Drug Administration-approved PET imaging agent (18)F-florbetapir may be used to target cardiac amyloidosis next.
Resorufin Analogs Preferentially Bind Cerebrovascular Amyloid: Potential Use as Imaging Ligands for Cerebral Amyloid Angiopathy.
Abstract
ABSTRACT:
BACKGROUND:
Cerebral amyloid angiopathy (CAA) is characterized by deposition of fibrillar amyloid beta (Abeta) within cerebral vessels. It is commonly seen in the elderly and almost universally present in patients with Alzheimer's Disease (AD). In both patient populations, CAA is an independent risk factor for lobar hemorrhage, ischemic stroke, and dementia. To date, definitive diagnosis of CAA requires obtaining pathological tissues via brain biopsy (which is rarely clinically indicated) or at autopsy. Though amyloid tracers labeled with positron-emitting radioligands such as [11C]PIB have shown promise for non-invasive amyloid imaging in AD patients, to date they have been unable to clarify whether the observed amyloid load represents neuritic plaques versus CAA due in large part to the low resolution of PET imaging and the almost equal affinity of these tracers for both vascular and parenchymal amyloid. Therefore, the development of a precise and specific non-invasive technique for diagnosing CAA in live patients is desired.
RESULTS:
We found that the phenoxazine derivative resorufin preferentially bound cerebrovascular amyloid deposits over neuritic plaques in the aged Tg2576 transgenic mouse model of AD/CAA, whereas the congophilic amyloid dye methoxy-X34 bound both cerebrovascular amyloid deposits and neuritic plaques. Similarly, resorufin-positive staining was predominantly noted in fibrillar Abeta-laden vessels in postmortem AD brain tissues. Fluorescent labeling and multi-photon microscopy further revealed that both resorufin- and methoxy-X34-positive staining is colocalized to the vascular smooth muscle (VSMC) layer of vessel segments that have severe disruption of VSMC arrangement, a characteristic feature of CAA. Resorufin also selectively visualized vascular amyloid deposits in live Tg2576 mice when administered topically, though not systemically. Resorufin derivatives with chemical modification at the 7-OH position of resorufin also displayed a marked preferential binding affinity for CAA, but with enhanced lipid solubility that indicates their use as a non-invasive imaging tracer for CAA is feasible.
CONCLUSIONS:
To our knowledge, resorufin analogs are the fist class of amyloid dye that can discriminate between cerebrovascular and neuritic forms of amyloid. This unique binding selectivity suggests that this class of dye has great potential as a CAA-specific amyloid tracer that will permit non-invasive detection and quantification of CAA in live patients.
Automatic segmentation of amyloid plaques in MR images using unsupervised support vector machines.
Source
Center for Basic MR Research, NorthShore University HealthSystem, Evanston, Illinois, USA. george.iordanescu@gmail.com.
Abstract
Deposition of the β-amyloid peptide (Aβ) is an important pathological hallmark of Alzheimer's disease (AD). However, reliable quantification of amyloid plaques in both human and animal brains remains a challenge. We present here a novel automatic plaque segmentation algorithm based on the intrinsic MR signal characteristics of plaques. This algorithm identifies plaque candidates in MR data by using watershed transform, which extracts regions with low intensities completely surrounded by higher intensity neighbors. These candidates are classified as plaque or nonplaque by an unsupervised learning method using features derived from the MR data intensity. The algorithm performance is validated by comparison with histology. We also demonstrate the algorithm's ability to detect age-related changes in plaque load ex vivo in amyloid precursor protein (APP) transgenic mice that coexpress five familial AD mutations (5xFAD mice). To our knowledge, this study represents the first quantitative method for characterizing amyloid plaques in MRI data. The proposed method can be used to describe the spatiotemporal progression of amyloid deposition, which is necessary for understanding the evolution of plaque pathology in mouse models of Alzheimer's disease and to evaluate the efficacy of emergent amyloid-targeting therapies in preclinical trials. Magn Reson Med, 2011. © 2011 Wiley-Liss, Inc.
Copyright © 2011 Wiley-Liss, Inc.
Amyloid pathology in persons with "normal" cognition.
Source
From the Rush Alzheimer's Disease Center, Department of Neurological Sciences, Rush University Medical Center, Chicago, IL.
Abstract
Alzheimer disease (AD) is characterized pathologically by cortical neuritic plaques composed of a central core ofamyloid-β (Aβ) peptide fibrils and neurofibrillary tangles composed of abnormally phosphorylated tau. The deposition of Aβ is thought to be an early step in a cascade of events that ultimately leads to the loss of cognitive abilities and dementia that characterizes AD. Thus, it was not surprising to find AD pathology in persons with mild cognitive impairment (MCI).(1) Clinical-pathologic studies have also reported a relation between AD pathology and cognition in persons without MCI or dementia.(2) Over the past several years, clinical-pathologic studies have been confirmed with in vivo imaging of amyloid by PET using Pittsburgh compound B (PiB).(3) Overall, these findings have led to a new conceptualization of AD as beginning with an asymptomatic pathophysiologic process, followed by a MCI stage, and ultimately the final AD dementia stage.(4,5) Understanding factors that influence the onset and progression of AD is of great interest. The apolipoprotein E ε4 allele polymorphism (APOE) is the most important genetic risk factor for AD and may increase disease risk, in part, by influencing Aβ clearance and fibrillogenesis.(6) In fact, some clinical-pathologic data suggest that Aβ mediates the association of APOE with cognition, at least in studies that include the full range of cognition.(7) However, the influence of APOE on Aβ and cognition among persons without cognitive impairment has not been well studied. In this issue of Neurology®, Kantarci et al.(8) use data from the Mayo Clinic Study of Aging (MCSA) to examine the relation of APOE to Aβ identified by PiB PET imaging and cognitive function in persons without cognitive impairment.
Amyloid generation and dysfunctional immunoproteasome activation with disease progression in animal model of familial Alzheimer disease.
Source
Institut de Neuropatologia, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, Hospitalet de Llobregat; CIBERNED (Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas); Spain Dipartimento di Biologia Animale, Laboratorio di Biologia Cellulare e Neurobiologia, Università di Pavia, Pavia, Italy Laboratorio de Fisiología y Biofísica de Membranas, Departamento de Biología Animal & Instituto de Tecnologías Biomédicas, Universidad de La Laguna, Tenerife, Spain Departament de Medicina Experimental, Universitat de Lleida-IRBLleida, Lleida, Spain Centre de Genètica Mèdica i Molecular, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.
Abstract
Double-transgenic APP/PS1 mice express a chimeric mouse/human amyloid precursor protein (APP) bearing the Swedish mutation (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9) both causative of familial Alzheimer disease (FAD). Transgenic mice show impaired memory and learning performance from the age of six months onwards. Double-transgenic APP/PS1 mice express altered APP and PS1 mRNAs and proteins, reduced BACE1 mRNA and normal BACE1 protein, all of which suggest a particular mechanism of amyloidogenesis when compared with sporadic AD. The first β-amyloid plaques in APP/PS1 mice appear at three months and they increase in number and distribution with disease progression in parallel with increased levels of brain soluble β-amyloid 1-42 and 1-40, but also with reduced 1-42/1-40 ratio with age. Amyloid deposition in plaques is accompanied by altered mitochondria and increased oxidative damage, post-translational modifications and accumulation of altered proteins at the dystrophic neurites surroundingplaques. Degradation pathways are also modified with disease progression including activation of the immunoproteasome together with variable alterations of the different protease activities of the ubiquitin-proteasome system. Present observations show modifications in the production of β-amyloid, and activation and malfunction of the subcellular degradation pathways that have general implications in the pathogenesis of AD and more particularly in specificities of FAD amyloidogenesis.
© 2011 The Authors; Brain Pathology © 2011 International Society of Neuropathology.
β-amyloid peptide binds and regulates ectopic ATP synthase α-chain on neural surface.
Source
aShanghai Geriatric Institute of Chinese Medicine , Shanghai 200031 , PR China.
Abstract
Abstract Accumulation of the amyloid β protein (Aβ) in the brain is an important step in the pathogenesis of Alzheimer's disease. Many molecules could bind with Aβ, among which some molecules mediate Aβ neuronal toxicity. Thus, it is of interest to study the binding proteins of Aβ, which functions might be affected by Aβ. In present study, we observed that accumulation of α-subunit of ATP synthase associated with aggregates of Aβ proteins in amyloid plaques of amyloidprecursor protein/presennillin-1 (APP/PS1) transgenic mice, and identified the α-subunit of ATP synthase as one of Aβ binding proteins on the plasma membrane of neural cells by Western blot and mass spectrometry. In order to evaluate the consequences of the interaction between Aβ and surface α-subunit of ATP synthase, the extracellular ATP generation was analyzed which showed that aggregated Aβ partially inhibited the extracellular generation of ATP, but was unable to induce a decrease of cell surface ATP synthase α on neurons significantly. These results suggest that the cell surface ATP synthase α is a binding protein for Aβ on neural cells, the functional inhibition of surface ATP synthase might be involved in machinery of brain malfunction in Aβ mediated pathogenesis of Alzheimer's disease.
Propyl isomerase Pin1 promotes APP protein turnover by inhibiting GSK3β kinase activity: A novel mechanism for Pin1 to protect against Alzheimer's disease.
Source
Beth Israel Deaconese Medical Center, United States;
Abstract
Alzheimer's disease (AD) is characterized by the presence of senile plaques of amyloid-beta peptides (Aβ) derived fromamyloid precursor protein (APP) and neurofibrillary tangles composed of hyperphosphorylated tau. Increasing APP gene dosage or expression has been shown to cause familial early-onset AD. However, whether protein stability of APP is regulated is unclear. The prolyl isomerase Pin1 and glycogen synthase 3β (GSK3β) have been shown to have the opposite effects on APP processing and tau hyperphosphorylation, relevant to the pathogenesis of AD. However, nothing is known about their relationship. In this study, we found that Pin1 binds to the pT330-P motif in GSK3β to inhibit its kinase activity. Furthermore, Pin1 promotes protein turnover of APP by inhibiting GSK3β activity. A point mutation either at T330, the Pin1-binding site in GSK3β, or T668, the GSK3β phosphorylation site in APP, abolished the regulation of GSK3β activity, T668 phosphorylation and APP stability by Pin1, resulting in reduced non-amyloidogenic APP processing and increased APP levels. These results uncover a novel role of Pin1 in inhibiting GSK3β kinase activity to reduce APP protein levels, providing a previously unrecognized mechanism by which Pin1 protects against Alzheimer's disease.
Localization of mature neprilysin in lipid rafts.
Source
Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan.
Abstract
Alzheimer's disease (AD) is characterized by senile plaques caused by amyloid-β peptide (Aβ) accumulation. It has been reported that Aβ generation and accumulation occur in membrane microdomains, called lipid rafts, which are enriched in cholesterol and glycosphingolipids. Moreover, the ablation of cholesterol metabolism has been implicated in AD. Neprilysin (NEP), a neutral endopeptidase, is one of the major Aβ-degrading enzymes in the brain. Activation of NEP is a possible therapeutic target. However, it remains unknown whether the activity of NEP is regulated by its association with lipid rafts. Here we show that only the mature form of NEP, which has been glycosylated in the Golgi, exists in lipid rafts, where it is directly associated with phosphatidylserine. Moreover, the localization of NEP in lipid rafts is enhanced by its dimerization, as shown using the NEP E403C homodimerization mutant. However, the protease activities of the mature form of NEP, as assessed by in vitro peptide hydrolysis, did not differ between lipid rafts and nonlipid rafts. We conclude that cholesterol and other lipids regulate the localization of mature NEP to lipid rafts, where the substrate Aβ accumulates but does not modulate the protease activity of NEP. © 2011 Wiley-Liss, Inc.
Copyright © 2011 Wiley-Liss, Inc.
p75NTR is mainly responsible for Aβ toxicity but not for its internalization: a primary study.
Source
Department of Human Physiology and Centre for Neuroscience, Flinders University, GPO Box 2100, Adelaide, 5001, Australia, yuhlzjl@ccmu.edu.cn.
Abstract
Accumulating evidence indicates that the intraneuronal accumulation of beta-amyloid peptide (Aβ) is earlier than the formation of extraneuronal amyloid plaque but the mechanism of the accumulation remains unclear. p75NTR is a receptor for Aβ and interacts with Aβ in vitro and in vivo but whether p75NTR mediates Aβ internalization and intraneuronal accumulation is not known. In this study, we aim to determine if p75NTR mediates Aβ internalization, which might provide new insights into Aβ metabolism and toxicity. FRET analysis in PC12 cells showed that internalized Aβ was close to p75NTR. Aβ1-42 could be internalized in PC12 cells in a concentration-dependent manner but the antibody to the p75NTR extracellular domain did not prevent its internalization. Aβ1-42 could also be internalized in mouse neonatal cortical neurons and the deletion of p75NTR in these neurons did not prevent its internalization but prevented Aβ neurotoxicity. Cholesterol at 10 μM significantly increased Aβ1-42 internalization in PC12 cells. Internalized Aβ1-42 is mainly co-localized with Beclin-1 (a biomarker of autophagosomes) but not with endosomal and lysomal markers. p75NTR may not play a main role in Aβ internalization at the concentrations tested but is responsible for Aβ induced toxicity in primary neurons. Internalized Aβ is mainly sorted to autophagosomes for metabolism.
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