1.
Evidence for Astrocytosis in Prodromal Alzheimer Disease Provided by 11C-Deuterium-L-Deprenyl: A Multitracer PET Paradigm Combining 11C-Pittsburgh Compound B and 18F-FDG.
Source
Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
Abstract
Astrocytes colocalize with fibrillar amyloid-β (Aβ) plaques in postmortem Alzheimer disease (AD) brain tissue. It is therefore of great interest to develop a PET tracer for visualizing astrocytes in vivo, enabling the study of the regional distribution of both astrocytes and fibrillar Aβ. A multitracer PET investigation was conducted for patients with mild cognitive impairment (MCI), patients with mild AD, and healthy controls using (11)C-deuterium-L-deprenyl ((11)C-DED) to measure monoamine oxidase B located in astrocytes. Along with (11)C-DED PET, (11)C-Pittsburgh compound B ((11)C-PIB; fibrillar Aβ deposition), (18)F-FDG (glucose metabolism), T1 MRI, cerebrospinal fluid, and neuropsychologic data were acquired from the patients.
METHODS:
(11)C-DED PET was performed in MCI patients (n = 8; mean age ± SD, 62.6 ± 7.5 y; mean Mini Mental State Examination, 27.5 ± 2.1), AD patients (n = 7; mean age, 65.1 ± 6.3 y; mean Mini Mental State Examination, 24.4 ± 5.7), and healthy age-matched controls (n = 14; mean age, 64.7 ± 3.6 y). A modified reference Patlak model, with cerebellar gray matter as a reference, was chosen for kinetic analysis of the (11)C-DED data. (11)C-DED data from 20 to 60 min were analyzed using a digital brain atlas. Mean regional (18)F-FDG uptake and (11)C-PIB retention were calculated for each patient, with cerebellar gray matter as a reference.
RESULTS:
ANOVA analysis of the regional (11)C-DED binding data revealed a significant group effect in the bilateral frontal and bilateral parietal cortices related to increased binding in the MCI patients. All patients, except 3 with MCI, showed high (11)C-PIB retention. Increased (11)C-DED binding in most cortical and subcortical regions was observed in MCI (11)C-PIB+ patients relative to controls, MCI (11)C-PIB (negative) patients, and AD patients. No regional correlations were found between the 3 PET tracers.
CONCLUSION:
Increased (11)C-DED binding throughout the brain of the MCI (11)C-PIB+ patients potentially suggests that astrocytosis is an early phenomenon in AD development.
- PMID:
- 22213821
- [PubMed - in process]
Cerebrospinal Fluid Levels of β-Amyloid 1-42, but Not of Tau, Are Fully Changed Already 5 to 10 Years Before the Onset of Alzheimer Dementia.
Source
Neuropsychiatric Clinic, Skåne University Hospital, S-20502 Malmö, Sweden. oskar.hansson@med.lu.se.
Abstract
CONTEXT:
Early detection of prodromal Alzheimer disease (AD) is important because new disease-modifying therapies are most likely to be effective when initiated during the early stages of disease.
OBJECTIVES:
To assess the ability of the cerebrospinal fluid (CSF) biomarkers total tau (T-tau), phosphorylated tau (P-tau), and β-amyloid 1-42 (Aβ42) to predict future development of AD dementia within 9.2 years in patients with mild cognitive impairment (MCI) and to compare CSF biomarkers between early and late converters to AD.
DESIGN:
A clinical study with a median follow-up of 9.2 years (range, 4.1-11.8 years).
SETTING:
Memory disorder clinic. Patients A total of 137 patients with MCI who underwent lumbar puncture at baseline. Main Outcome Measure Conversion to AD dementia.
RESULTS:
During follow-up, 72 patients (53.7%) developed AD and 21 (15.7%) progressed to other forms of dementia. At baseline, CSF Aβ42 levels were reduced and T-tau and P-tau levels were elevated in patients who converted to AD during follow-up compared with nonconverters (P < .001). Baseline CSF Aβ42 levels were equally reduced in patients with MCI who converted to AD within 0 to 5 years (early converters) compared with those who converted between 5 and 10 years (late converters). However, CSF T-tau and P-tau levels were significantly higher in early converters vs late converters. A baseline Aβ42:P-tau ratio predicted the development of AD within 9.2 years with a sensitivity of 88%, specificity of 90%, positive predictive value of 91%, and negative predictive value of 86%.
CONCLUSIONS:
Approximately 90% of patients with MCI and pathologic CSF biomarker levels at baseline develop AD within 9 to 10 years. Levels of Aβ42 are already fully decreased at least 5 to 10 years before conversion to AD dementia, whereas T-tau and P-tau seem to be later markers. These results provide direct support in humans for the hypothesis that altered Aβ metabolism precedes tau-related pathology and neuronal degeneration.
- PMID:
- 22213792
- [PubMed - in process]
Isolation of synaptic terminals from Alzheimer's disease cortex.
Source
UCLA School of Nursing, Los Angeles, California 90095; UCLA Center for the Advancement of Gerontological Nursing Sciences, Los Angeles, California 90095; UCLA Brain Research Institute, Los Angeles, California 90095. ssokolow@sonnet.ucla.edu.
Abstract
Amyloid beta (Aβ) oligomers and phosphorylated tau (p-tau) aggregates are increasingly identified as potential toxic intermediates in Alzheimer's disease (AD). In cortical AD synapses, p-tau co-localizes with Aβ, but the Aβ and p-tau peptide species responsible for synaptic dysfunction and demise remains unclear. The present experiments were designed to use high-speed cell sorting techniques to purify synaptosome population based on size, and then extend the method to physically isolate Aβ-positive synaptosomes with the goal of understanding the nature of Aβ and tau pathology in AD synapses. To examine the purity of size-gated synaptosomes, samples were first gated on size; particles with sizes between 0.5 and 1.5 microns were collected. Electron microscopy documented a homogenous population of spherical particles with internal vesicles and synaptic densities. Next, size-gated synaptosomes positive for Aβ were collected by fluorescence activated sorting and then analyzed by immunoblotting techniques. Sorted Aβ-positive synaptosomes were enriched for amyloid precursor protein (APP) and for Aβ oligomers and aggregates; immunolabeling for p-tau showed a striking accumulation of p-tau aggregates compared to the original homogenate and purified synaptosomes. These results confirm co-localization of Aβ and p-tau within individual synaptic terminals and provide proof of concept for the utility of flow sorting synaptosomes. © 2011 International Society for Advancement of Cytometry.
Copyright © 2011 International Society for Advancement of Cytometry.
- PMID:
- 22213704
- [PubMed - as supplied by publisher]
Inflammatory cerebral amyloid angiopathy: the overlap of perivascular (PAN-like) with vasculitic (Aβ-related angiitis) form: an autopsy case.
Source
Grażyna Maria Szpak, Department of Neuropathology, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957 Warsaw, Poland, e-mail: szpak@ipin.edu.pl.
Abstract
Beside advanced age, cerebral amyloid angiopathy (CAA) and hypertension (HTA) are the two most important risk factors for haemorrhagic stroke. Inflammatory changes of amyloid-laden vessels have been reported only in rare sporadic CAA cases. We present the case of a 78-year-old woman with a history of hypertension, dementia and haemorrhagic stroke of the right frontal lobe 2 years before admission. She was admitted with recurrence of symptoms of transient aphasia and central, right-side facial paresis that occurred an hour before her arrival at the hospital. In the admission unit, she was only slightly confused, with no other neurological deficits. An urgent CT scan revealed a recent haemorrhagic stroke in the left frontal lobe. In an hour her condition suddenly deteriorated. After a generalized seizure she presented with right-side hemiparesis with signs of uncal herniation and remained unconscious. A control CT scan showed a large haemorrhagic expansion that comprised the whole left brain hemisphere with 2 cm midline shift. She died about 10 hours after the onset of symptoms. At autopsy chronic inflammation of the thyroid gland, bronchopneumonia, fibrous and fatty heart degeneration and kidney haemorrhagic infarcts were documented. Amyloid deposition and systemic immune disorders in the inner organs were not demonstrated. In neuropathological examination we diagnosed inflammatory form of CAA with coexistence (the overlap) of two, perivascular and vascular, subtypes of CAA-related inflammation.
- PMID:
- 22212924
- [PubMed - in process]
Immunodistribution of amyloid beta protein (Aβ) and advanced glycation end-product receptors (RAGE) in choroid plexus and ependyma of resuscitated patients.
Source
Prof. Danuta Maślińska, Department of Experimental and Clinical Neuropathology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawińskiego St, 02-106 Warsaw, Poland, phone +48 22 608 65 02, fax +48 22 608 65 02, e-mail: maslinskad@cmdik.pan.pl.
Abstract
RAGE (receptor for advanced glycation end-products) participates in the influx transport of glycated Aβ (amyloid beta) from the blood to the brain. Because little is known of the RAGE operating in brain barriers such as those in the choroid plexus and ependyma, the aim of the present study was to examine the immunodistributions of RAGE and Aβ peptides in the choroid plexus where the blood-cerebrospinal fluid barrier (B-CSF) is located, and in ependyma of the brain ventricles associated with functions of the cerebrospinal fluid-brain barrier (CSF-B). The study was performed on patients over 65 years successfully resuscitated after cardiac arrest with survival a few weeks. The control group consisted of age-matched individuals who were not resuscitated and died immediately after cardiac arrest. In resuscitated patients, but not in controls, RAGE receptors were localized in choroid plexus (CP) epithelial cells and in ependymal cells bordering the brain ventricles. These cells form the B-CSF and CSF-B barriers. The presence of Aβ was detected within the CP blood vessels and in the basement membrane of the CP epithelium. In numerous cytoplasmic vacuoles of CP epithelial and ependymal cells Aβ protein was found and our observations suggest that the contents of those vacuoles were undergoing progressive digestion. The results demonstrated that CP epithelium and ependymal cells, equipped with RAGE receptors, not only play an important role in the creation of amyloid deposits in the brain but are also places where Aβ may be utilized. The RAGE transportation system should be a main target in the therapy of brain amyloidosis, a well-known risk factor of Alzheimer disease.
- PMID:
- 22212919
- [PubMed - in process]
Reserpine modulates neurotransmitter release to extend lifespan and alleviate age-dependent Aβ proteotoxicity in Caenorhabditis elegans.
Abstract
Aging is a debilitating process often associated with chronic diseases such as diabetes, cardiovascular and neurodegenerative diseases like Alzheimer's disease (AD). AD occurs at a very high incidence posing a huge burden to the society. Model organisms such as C. elegans become essential to understand aging or lifespan extension - the etiology, molecular mechanism and identification of new drugs against age associated diseases. The AD model, manifesting Aβ proteotoxicity, in C. elegans is well established and has provided valuable insights. Earlier, we have reported that Reserpine, an FDA-approved antihypertensive drug, increases C. elegans lifespan with a high quality of life and ameliorates Aβ toxicity in C. elegans. But reserpine does not seem to act through the known lifespan extension pathways or inhibition of its known target, vesicular monoamine transporter, VMAT. Reserpine's mode of action and the pathways it activates are not known. Here, we have evaluated the presynaptic neurotransmitter(s) release pathway and identified acetylcholine (ACh) as the crucial player for reserpine's action. The corroborating evidences are: i) lack of lifespan extension in the ACh loss of function (hypomorphic) - synthesis (cha-1) and transport (unc-17) mutants; ii) mitigation of chronic aldicarb effect; iii) lifespan extension in dopamine (cat-2) and dopamine and serotonin (bas-1) biosynthetic mutants; iv) no rescue from exogenous serotonin induced paralysis in the AD model worms; upon reserpine treatment. Thus, modulation of acetylcholine is essential for reserpine's action.
Copyright © 2011. Published by Elsevier Inc.
- PMID:
- 22212533
- [PubMed - as supplied by publisher]
The early events of Alzheimer's disease pathology: from mitochondrial dysfunction to BDNF axonal transport deficits.
Source
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Abstract
Although there are numerous studies regarding Alzheimer's disease (AD), the cause and progression of AD are still not well understood. The researches in the past decade implicated amyloid-beta (Aβ) overproduction as a causative event in disease pathogenesis, but still failed to clarify the mechanism of pathology from Aβ production to central neural system defects in AD. The present review raises the hypothesis that the onset of AD pathology is closely related with mitochondrial dysfunction induced by Aβ and brain-derived neurotrophic factor (BDNF) axonal transport deficits. It is well-known that axonal transport defect and attenuation of BDNF-neurotrophic tyrosine receptor kinase 2 (TrkB) signal are fatal to neuronal function and survival. We hypothesized that abnormal amyloid precursor protein (APP) processing and Aβ production in mitochondria disturb the axonal transport by impairing mitochondrial function and attenuate BDNF-neurotrophic tyrosine receptor kinase 2 signal subsequently. For this hypothesis, the factors related with the initiation of AD pathology are not only limited to the neurons per se but also expanded to the microenvironment around neurons, such as the secretion of BDNF from astrocytes. The modification of the origin in this pathway may contribute to slow down the disease progression of AD.
Copyright © 2011 Elsevier Inc. All rights reserved.
- PMID:
- 22212405
- [PubMed - as supplied by publisher]
Management of moderate to severe Alzheimer's disease: Focus on memantine.
Source
Department of Bioscience Technology, Chung Yuan Christian University, Chung Li, Taiwan.
Abstract
Alzheimer's disease (AD) is the most common form of dementia, and one of the principal causes leading to death around the world. It is a progressive neurodegenerative disorder that still remains without definite cure. Memantine, a licensed AD drug, is an open-channel and partial trapping blocker that functions as a potent NMDA receptor antagonist, even at low concentrations. Aside from being uncompetitive, it also allows near-normal physiological NMDA receptor activity throughout the brain even with high glutamate concentrations, making it more reliable and tolerable than other AD-targeted drugs. It has also been found to be effective, safe, and well-tolerated in animal models as well as patients with moderate-to-severe AD. Aside from NMDA receptor antagonism, numerous studies have reported that memantine can also affect dopamine receptors, block excessive calcium influx and production of reactive oxygen species (ROS) induced by Aβ oligomers, and inhibit the internal ribosome entry site (IRES), thus preventing the expression of the amyloid precursor and tau proteins which are considered as early indicators of Alzheimer's.
Copyright © 2011. Published by Elsevier B.V.
- PMID:
- 22212311
- [PubMed - in process]
Control of BACE1 degradation and APP processing by ubiquitin carboxyl-terminal hydrolase L1.
Source
Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, Graduate Program in Neuroscience, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada. Department of Degenerative Neurological Diseases, National Institute of Neuroscience, NCNP, Kodaira, Tokyo, 187-8502, Japan.
Abstract
Deposition of amyloid β protein (Aβ) in the brain is the hallmark of Alzheimer's Disease (AD) pathogenesis. Beta-site APP cleaving enzyme 1 (BACE1) is the β-secretase in vivo essential for generation of Aβ. Previously we demonstrated that BACE1 is ubiquitinated and the degradation of BACE1 is mediated by the ubiquitin-proteasome pathway (UPP). However the mechanism underlying regulation of BACE1 degradation by UPP remains elusive. Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme highly specific to neuron, catalyzing the hydrolysis of ubiquitin conjugates from ubiquitinated substrates. UCHL1 regulates ubiquitin-dependent protein degradation. However, whether UCHL1 is particularly involved in the proteasomal degradation of BACE1 and what is the role of UCHL1 in AD pathogenesis remain elusive. To investigate the effect of UCHL1 on BACE1 degradation, HUCH cells, a UCHL1 stably-overexpressed HEK293 cell line, was established. We found that inhibition of UCHL1 significantly increased BACE1protein level in a time-dependent manner. Half life of BACE1 was reduced in HUCH cells compared to HEK. Over expression of UCHL1 decreased APP C-terminal fragment C99 and Aβ levels in HUCH cells. Moreover, disruption of Uchl1 gene significantly elevated levels of endogenous BACE1, C99 and Aβ in the Uchl1-null gad mice. These results demonstrated that UCHL1 accelerates BACE1 degradation and affects APP processing and Aβ production. Our study suggests that potentiation of UCHL1 might be able to reduce the level of BACE1 and Aβ in brain, which makes it a novel target for AD drug development. © 2011 The Authors Journal of Neurochemistry© 2011 International Society for Neurochemistry.
© 2011 The Authors Journal of Neurochemistry © 2011 International Society for Neurochemistry.
- PMID:
- 22212137
- [PubMed - as supplied by publisher]
Obovatol improves cognitive functions in animal models for Alzheimer's disease.
Source
College of Pharmacy and MRC, Chungbuk National University, 12 Gaesin-dong, Heungduk-gu, Cheongju, Chungbuk, 361-763 South Korea Department of Food and Biotechnology, Chungju National University, 123 Geomdan-ri, Iryu-myeon, Chungju, Chungbuk, 380-702 South Korea KT&G Central Research Institute, Yuseong-gu, Daejeon, 305-805 South Korea Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, 305-333 South Korea.
Abstract
Etiology of Alzheimer's disease (AD) is obscure, but neuroinflammation and accumulation of β-amyloid (Aβ) are implicated in pathogenesis of AD. We have shown anti-inflammatory and neurotrophic properties of obovatol, a biphenolic compound isolated from Magnolia obovata. Here, we examined the effect of obovatol on cognitive deficits in two separate AD models; (1) mice that received intracerebroventricular (i.c.v.) infusion of Aβ(1-42) (2.0 μg/mouse) and (2) Tg2576 mice expressing mutant human amyloid precursor protein (APP; K670N, M671L). Injection of Aβ(1-42) into lateral ventricle caused memory impairments in the Morris water maze and passive avoidance tasks, being associated with neuroinflammation. Aβ(1-42) -induced abnormality was significantly attenuated by administration of obovatol. When we analyzed with Tg2576 mice, long-term treatment of obovatol (1 mg/kg/day for 3 months) significantly improved cognitive function. In parallel with the improvement, treatment suppressed astroglial activation, BACE1 expression and NF-κB activity in the transgenic mice. Furthermore, obovatol potently inhibited fibrillation of Aβin vitro in a dose-dependent manner, as determined by Thioflavin T fluorescence and electron microscopic analysis. In conclusion, our data demonstrated that obovatol prevented memory impairments in experimental AD models, which could be attributable to amelioration of neuroinflammation and amyloidogenesis by inhibition of NF-κB signaling pathway and anti-fibrillogenic activity of obovatol. © 2011 The Authors Journal of Neurochemistry© 2011 International Society for Neurochemistry.
Journal of Neurochemistry © 2011 International Society for Neurochemistry.
- PMID:
- 22212065
- [PubMed - as supplied by publisher]
Leukocyte Telomere Length (LTL) is reduced in stable mild cognitive impairment but low LTL is not associated with conversion to Alzheimer's Disease: A pilot study.
Source
Institute of Medicine, Department of Internal Medicine, the Sahlgrenska Academy, University of Gothenburg, S-41345 Gothenburg, Sweden.
Abstract
Leukocyte telomere length (LTL) is associated with the aging process and may be related to cognitive aging. Previous studies have shown conflicting results whether LTL is affected in patients with Alzheimer's disease (AD). In this pilot study, we investigated LTL in a well-defined homogeneous mono-center population. Sixty consecutive patients admitted for cognitive impairment to a memory clinic were recruited. The participants included patients with AD or mild cognitive impairment (MCI) diagnosed with AD upon follow-up (n=32), patients with stable MCI (n=13), patients with other dementias diagnosed at primary evaluation or upon follow-up (n=15), and healthy controls (n=20). LTL was determined using a quantitative PCR assay. Patients with AD had similar LTL as healthy controls. Patients with stable MCI had reduced LTL both compared to AD patients (p=0.02) and controls (p=0.008). Subanalyses within the AD group showed that patients with MCI that later converted to AD had similar LTL as patients with clinical diagnosis of AD at primary evaluation and healthy controls whereas the LTL was longer compared to the stable MCI group (p=0.02). There were no correlations between LTL and the core AD biomarkers Aβ(1-42), T-tau and P-tau. In conclusion, in this pilot study, patients with AD or MCI that later converted to AD had similar LTL as healthy controls. Patients with stable MCI that did not progress to dementia had reduced LTL compared to controls, which might suggest a more marked biological aging as a cause of the cognitive symptoms in this group.
Copyright © 2011. Published by Elsevier Inc.
Microglial activation and TDP-43 pathology correlate with executive dysfunction in amyotrophic lateral sclerosis.
Source
Center for Neurodegenerative Disease Research (CNDR), University of Pennsylvania School of Medicine, 3rd Floor Maloney Building, 3600 Spruce Street, Philadelphia, PA, 19104, USA.
Abstract
While cognitive deficits are increasingly recognized as common symptoms in amyotrophic lateral sclerosis (ALS), the underlying histopathologic basis for this is not known, nor has the relevance of neuroinflammatory mechanisms and microglial activation to cognitive impairment (CI) in ALS been systematically analyzed. Staining for neurodegenerative disease pathology, TDP-43, and microglial activation markers (CD68, Iba1) was performed in 102 autopsy cases of ALS, and neuropathology data were related to clinical and neuropsychological measures. ALS with dementia (ALS-D) and ALS with impaired executive function (ALS-Ex) patients showed significant microglial activation in middle frontal and superior or middle temporal (SMT) gyrus regions, as well as significant neuronal loss and TDP-43 pathology in these regions. Microglial activation and TDP-43 pathology in middle frontal and superior or middle temporal regions were highly correlated with measures of executive impairment, but not with the MMSE. In contrast, only one ALS-D patient showed moderate Alzheimer's disease (AD) pathology. Tau and Aβ pathology increased with age. A lower MMSE score correlated with tau pathology in hippocampus and SMT gyrus, and with Aβ pathology in limbic and most cortical regions. Tau and Aβ pathology did not correlate with executive measures. We conclude that microglial activation and TDP-43 pathology in frontotemporal areas are determinants of FTLD spectrum dementia in ALS and correlate with neuropsychological measures of executive dysfunction. In contrast, AD pathology in ALS is primarily related to increasing age and associated with a poorer performance on the MMSE.
Trans fatty acids enhance amyloidogenic processing of the Alzheimer amyloid precursor protein (APP).
Source
Deutsches Institut für DemenzPrävention (DIDP), Neurodegeneration and Neurobiology, 66421 Homburg, Germany.
Abstract
Hydrogenation of oils and diary products of ruminant animals leads to an increasing amount of trans fatty acids in the human diet. Trans fatty acids are incorporated in several lipids and accumulate in the membrane of cells. Here we systematically investigate whether the regulated intramembrane proteolysis of the amyloid precursor protein (APP) is affected by trans fatty acids compared to the cis conformation. Our experiments clearly show that trans fatty acids compared to cis fatty acids increase amyloidogenic and decrease nonamyloidogenic processing of APP, resulting in an increased production of amyloid beta (Aβ) peptides, main components of senile plaques, which are a characteristic neuropathological hallmark for Alzheimer's disease (AD). Moreover, our results show that oligomerization and aggregation of Aβ are increased by trans fatty acids. The mechanisms identified by this in vitro study suggest that the intake of trans fatty acids potentially increases the AD risk or causes an earlier onset of the disease.
Copyright © 2012 Elsevier Inc. All rights reserved.
Investigating the Neural Correlates of Pathological Cortical Networks in Alzheimer's Disease using Heterogeneous Neuronal Models.
Abstract
This paper describes an investigation into the pathophysiological causes of abnormal cortical oscillations in Alzheimer's disease (AD) using two heterogeneous neuronal network models. The effect of excitatory circuit disruption on the beta band power (13-30 Hz) using a conductance-based network model of 200 neurons is assessed. Then, the neural correlates of abnormal cortical oscillations in different frequency bands based on a larger network model of 1000 neurons consisting of different types of cortical neurons is also analyzed. Electroencephalography (EEG) studies in AD patients have shown that beta band power (13-30 Hz) decreased in the early stages of the disease with a parallel increase in theta band power (4-7 Hz). This abnormal change progresses with the later stages of the disease but with decreased power spectra in other fast frequency bands plus an increase in delta band power (1-3 Hz). Our results show that, despite the heterogeneity of the network models, the beta band power is significantly affected by excitatory neural and synaptic loss. Secondly, the results of modeling a functional impairment in the excitatory circuit shows that beta band power exhibits the most decrease compared with other bands. Previous biological experiments on different types of cultural excitatory neurons show that cortical neuronal death is mediated by dysfunctional ionic behavior that might specifically contribute to the pathogenesis of β-amyloid peptide (Aβ)-induced neuronal death in AD. Our study also shows that beta band power was the first affected component when the modeled excitatory circuit begins to lose neurons and synapses.
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 plaque formation, 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.
A new neuronal target for beta-amyloid peptide in the rat hippocampus.
Source
Centre de Psychiatrie et Neurosciences, UMR 894, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
Abstract
In Alzheimer's disease, amyloid beta peptide (Aβ) accumulation is associated with hippocampal network dysfunction. Intrahippocampal injections of Aβ induce aberrant inhibitory septohippocampal (SH) network activity in vivo and impairment of memory processing. In the present study, we observed, after hippocampal Aβ treatment, a selective loss of neurons projecting to the medial septum (MS) and containing calbindin (CB) and/or somatostatin (SOM). Other GABAergic neuronal subpopulations were not altered. Thus, the present study identifies hippocamposeptal neuron populations as specific targets for Aβ deposits. We observed that in Aβ-treated rats but not in controls, glutamate agonist application induced rhythmic bursting in 55% of the slow-firing neurons in the medial septum. This suggests that hippocampal Aβ can trigger modifications of the septohippocampal pathway via the alteration of a specific neuronal population. Long-range hippocamposeptal GABA/calbindin neurons, targets of hippocampal amyloid deposits, are implicated in supporting network synchronization. By identifying this target, we contribute to the understanding of the mechanisms underlying deleterious effects of Aβ, one of the main agents of dementia in Alzheimer's disease.
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.
Statins in Unconventional Secretion of Insulin-Degrading Enzyme and Degradation of the Amyloid-β Peptide.
Source
Department of Neurology, University of Bonn, Bonn, Germany.
Abstract
Population-based studies demonstrated that statins might decrease the risk of developing Alzheimer's disease (AD). Statins inhibit the 3-hydroxy-3-methyl-glutaryl-coenzyme-A reductase and thereby de novo synthesis of cholesterol. Cell culture and animal studies indicated that cholesterol affects the proteolytic processing of the amyloid precursor protein and the generation of amyloid-β (Aβ). Recently, we have demonstrated that statins can also stimulate the degradation of Aβ. The statin-induced clearance of Aβ could be attributed to increased release of the insulin-degrading enzyme (IDE) via an exosome-related unconventional secretory pathway. Interestingly, this statin-induced secretion of exosome-associated IDE was independent of cellular cholesterol concentrations, but rather caused by impairment of isoprenoid biosynthesis and protein prenylation. We further identified a new hexapeptide sequence in the C-terminal region of IDE, named the SlyX motif that is critically involved in IDE secretion. Taken these findings together, the increased clearance of Aβ by stimulated secretion of IDE might contribute to the protective effects of statins against AD.
Copyright © 2011 S. Karger AG, Basel.
Road to Alzheimer's Disease: The Pathomechanism Underlying.
Source
Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
Abstract
Alzheimer's disease (AD), the most common cause of dementia, results from the interplay of various deregulated mechanisms triggering a complex pathophysiology. The neurons suffer from and slowly succumb to multiple irreversible damages, resulting in cell death and thus memory deficits that characterize AD. In spite of our vast knowledge, it is still unclear as to when the disease process starts and how long the perturbations continue before the disease manifests. Recent studies provide sufficient evidence to prove amyloid β (Aβ) as the primary cause initiating secondary events, but Aβ is also known to be produced under normal conditions and to possess physiological roles, hence, the questions that remain are: What are the factors that lead to abnormal Aβ production? When does Aβ turn into a pathological molecule? What is the chain of events that follows Aβ? The answers are still under debate, and further insight may help us in creating better diagnostic and therapeutic options in AD. The present article attempts to review the current literature regarding AD pathophysiology and proposes a pathophysiologic cascade in AD.
No comments:
Post a Comment