Saturday, January 14, 2012

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1.
Arch Neurol. 2012 Jan;69(1):96-104.

Proteomic changes in cerebrospinal fluid of presymptomatic and affected persons carrying familial Alzheimer disease mutations.

Source

Mary S. Easton Center for Alzheimer's Disease Research, 10911 Weyburn Ave, Ste 200, Los Angeles, CA 90095. jringman@mednet.ucla.edu.

Abstract

OBJECTIVE:

To identify cerebrospinal fluid (CSF) protein changes in persons who will develop familial Alzheimer disease (FAD) due to PSEN1 and APP mutations, using unbiased proteomics.

DESIGN:

We compared proteomic profiles of CSF from individuals with FAD who were mutation carriers (MCs) and related noncarriers (NCs). Abundant proteins were depleted and samples were analyzed using liquid chromatography-electrospray ionization-mass spectrometry on a high-resolution time-of-flight instrument. Tryptic peptides were identified by tandem mass spectrometry. Proteins differing in concentration between the MCs and NCs were identified.

SETTING:

A tertiary dementia referral center and a proteomic biomarker discovery laboratory.

PARTICIPANTS:

Fourteen FAD MCs (mean age, 34.2 years; 10 are asymptomatic, 12 have presenilin-1 [PSEN1 ] gene mutations, and 2 have amyloid precursor protein [APP ] gene mutations) and 5 related NCs (mean age, 37.6 years).

RESULTS:

Fifty-six proteins were identified, represented by multiple tryptic peptides showing significant differences between MCs and NCs (46 upregulated and 10 downregulated); 40 of these proteins differed when the analysis was restricted to asymptomatic individuals. Fourteen proteins have been reported in prior proteomic studies in late-onset AD, including amyloid precursor protein, transferrin, α(1)β-glycoprotein, complement components, afamin precursor, spondin 1, plasminogen, hemopexin, and neuronal pentraxin receptor. Many other proteins were unique to our study, including calsyntenin 3, AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) 4 glutamate receptor, CD99 antigen, di- N-acetyl-chitobiase, and secreted phosphoprotein 1.

CONCLUSIONS:

We found much overlap in CSF protein changes between individuals with presymptomatic and symptomatic FAD and those with late-onset AD. Our results are consistent with inflammation and synaptic loss early in FAD and suggest new presymptomatic biomarkers of potential usefulness in drug development.

PMID:
22232349
[PubMed - in process]
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2.
J Biol Chem. 2012 Jan 4. [Epub ahead of print]

Tannic Acid is a Natural β-secretase Inhibitor that Prevents Cognitive Impairment and Mitigates Alzheimer-like Pathology in Transgenic Mice.

Source

Saitama Medical Center and University, Japan;

Abstract

Amyloid precursor protein (APP) proteolysis is essential for production of amyloid-β (Aβ) peptides that form β-amyloid plaques in brains of Alzheimer disease (AD) patients. Recent focus has been directed toward a group of naturally-occurring anti-amyloidogenic polyphenols known as flavonoids. We orally administered the flavonoid tannic acid (TA) to the transgenic PSAPP mouse model of cerebral amyloidosis (bearing mutant human APP and presenilin-1 transgenes) and evaluated cognitive function and AD-like pathology. Consumption of TA for 6 months prevented transgene-associated behavioral impairment including hyperactivity, decreased object recognition, and defective spatial reference memory, but did not alter non-transgenic mouse behavior. Accordingly, brain parenchymal and cerebral vascular β-amyloid deposits and abundance of various Aβ species including oligomers were mitigated in TA-treated PSAPP mice. These effects occurred with decreased cleavage of the β-carboxyl-terminal APP fragment, lowered soluble APP-β production, reduced β-site APP cleaving enzyme 1 protein stability and activity, and attenuated neuroinflammation. As in vitro validation, we treated well-characterized mutant human APP-overexpressing murine neuron-like cells with TA and found significantly reduced Aβ production associated with less amyloidogenic APP proteolysis. Taken together, these results raise the possibility that dietary supplementation with TA may be prophylactic for AD by inhibiting β-secretase activity and neuroinflammation and thereby mitigating AD pathology.

PMID:
22219198
[PubMed - as supplied by publisher]
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3.
J Nutr Biochem. 2011 Dec 29. [Epub ahead of print]

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.

PMID:
22209004
[PubMed - as supplied by publisher]
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4.
PLoS One. 2011;6(12):e28263. Epub 2011 Dec 14.

Hypoxia Due to Cardiac Arrest Induces a Time-Dependent Increase in Serum Amyloid β Levels in Humans.

Source

Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.

Abstract

Amyloid β (Aβ) peptides are proteolytic products from amyloid precursor protein (APP) and are thought to play a role inAlzheimer disease (AD) pathogenesis. While much is known about molecular mechanisms underlying cerebral Aβ accumulation in familial AD, less is known about the cause(s) of brain amyloidosis in sporadic disease. Animal and postmortem studies suggest that Aβ secretion can be up-regulated in response to hypoxia. We employed a new technology (Single Molecule Arrays, SiMoA) capable of ultrasensitive protein measurements and developed a novel assay to look for changes in serum Aβ42 concentration in 25 resuscitated patients with severe hypoxia due to cardiac arrest. After a lag period of 10 or more hours, very clear serum Aβ42 elevations were observed in all patients. Elevations ranged from approximately 80% to over 70-fold, with most elevations in the range of 3-10-fold (average approximately 7-fold). The magnitude of the increase correlated with clinical outcome. These data provide the first direct evidence in living humans that ischemia acutely increases Aβ levels in blood. The results point to the possibility that hypoxia may play a role in the amyloidogenic process of AD.

PMID:
22194817
[PubMed - in process]
PMCID: PMC3237426
Free PMC Article
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5.
Toxicol Lett. 2012 Feb 25;209(1):94-105. Epub 2011 Dec 8.

The miR-124 regulates the expression of BACE1/β-secretase correlated with cell death in Alzheimer's disease.

Source

Institute of Anatomy and Cell Biology, Medical College, Zhejiang University, Hangzhou, China.

Abstract

The role of miR-124 on the expression of β-site APP cleaving enzyme 1 (BACE1), an important cleavager of amyloid precursor protein that plays a pivotal role in the β-amyloid production, was studied in this paper using cellular models forAlzheimer' disease (AD) of cultured PC12 cell lines and primary cultured hippocampal neurons. The aim of the present study was to uncover novel potential miR-124 targets and shed light on its function in the cellular AD model. MiR-124 expression was steadily altered when its mimic and inhibitor were transfected in vitro. The results showed the expression of BACE1, one of the potential functional downstream targets of miR-124, was well correlated with cell death induced by Aβ neurotoxicity, and its expression level could be up- and down-regulated by suppression or over expression of miR-124 level respectively. These findings suggest that miR-124 may work as a basilic regulating factor to alleviate cell death in the process of AD by targeting BACE1, play an essential role in the control of BACE1 gene expression, and might be considered as a novel therapeutic target in treating AD.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

PMID:
22178568
[PubMed - in process]
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6.
FASEB J. 2011 Dec 15. [Epub ahead of print]

Mechanistic involvement of the calpain-calpastatin system in Alzheimerneuropathology.

Source

*Laboratory for Proteolytic Neuroscience, Rikagaku Kenkyūjo (RIKEN) Brain Science Institute, Wako, Saitama, Japan;

Abstract

The mechanism by which amyloid-β peptide (Aβ) accumulation causes neurodegeneration in Alzheimer's disease (AD) remains unresolved. Given that Aβ perturbs calcium homeostasis in neurons, we investigated the possible involvement of calpain, a calcium-activated neutral protease. We first demonstrated close postsynaptic association of calpain activation with Aβ plaque formation in brains from both patients with AD and transgenic (Tg) mice overexpressing amyloid precursor protein (APP). Using a viral vector-based tracer, we then showed that axonal termini were dynamically misdirected to calpain activation-positive Aβ plaques. Consistently, cerebrospinal fluid from patients with AD contained a higher level of calpain-cleaved spectrin than that of controls. Genetic deficiency of calpastatin (CS), a calpain-specific inhibitor protein, augmented Aβ amyloidosis, tau phosphorylation, microgliosis, and somatodendritic dystrophy, and increased mortality in APP-Tg mice. In contrast, brain-specific CS overexpression had the opposite effect. These findings implicate that calpain activation plays a pivotal role in the Aβ-triggered pathological cascade, highlighting a target for pharmacological intervention in the treatment of AD.-Higuchi, M., Iwata, N., Matsuba, Y., Takano, J., Suemoto, T., Maeda, J., Ji, B., Ono, M., Staufenbiel, M., Suhara, T., Saido, T. C. Mechanistic involvement of the calpain-calpastatin system in Alzheimer neuropathology.

PMID:
22173972
[PubMed - as supplied by publisher]
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7.
J Neuroinflammation. 2011 Dec 15;8(1):175. [Epub ahead of print]

Apolipoprotein E expression is elevated by interleukin 1 and other interleukin 1-induced factors.

Abstract

ABSTRACT:

BACKGROUND:

We have previously outlined functional interactions, including feedback cycles, between several of the gene products implicated in the pathogenesis of Alzheimer's disease. A number of Alzheimer-related stressors induce neuronal expression of apolipoprotein E (ApoE), beta-amyloid precursor protein (betaAPP), and fragments of the latter such as amyloid beta-peptide (Abeta) and secreted APP (sAPP). These stressors include interleukin-1 (IL-1)-mediated neuroinflammation and glutamate-mediated excitotoxicity. Such circumstances are especially powerful when they transpire in the context of an APOE epsilon4 allele.

METHODS:

Semi-quantitative immunofluorescence imaging was used to analyze rat brains implanted with IL-1beta slow-release pellets, sham pellets, or no pellets. Primary neuronal or NT2 cell cultures were treated with IL-1beta, glutamate, Abeta, or sAPP; relative levels of ApoE mRNA and protein were measured by RT-PCR, qRT-PCR, and western immunoblot analysis. Cultures were also treated with inhibitors of multi-lineage kinases--in particular MAPK-p38 (SB203580), ERK (U0126), or JNK (SP600125)--prior to exposure of cultures to IL-1beta, Abeta, sAPP, or glutamate.

RESULTS:

Immunofluorescence of tissue sections from pellet-implanted rats showed that IL-1beta induces expression of betaAPP, IL-1alpha, and ApoE; the latter was confirmed by western blot analysis. These protein changes were mirrored by increases in their mRNAs, as well as in those encoding IL-1beta, IL-1beta-converting enzyme (ICE), and tumor necrosis factor (TNF). IL-1beta also increased ApoE expression in neuronal cultures. It stimulated release of sAPP and glutamate in these cultures too, and both of these agents--as well as Abeta--stimulated ApoE expression themselves, suggesting that they may contribute to the effect of IL-1beta on ApoE levels. Inhibitors of MAPK-p38, ERK, and JNK inhibited ApoE induction by all these agents except glutamate, which was sensitive only to inhibitors of ERK and JNK.

CONCLUSION:

Conditions of glial activation and hyperexcitation can elevate proinflammatory cytokines, ApoE, glutamate, betaAPP, and its secreted fragments. Because each of these factors promotes glial activation and neuronal hyperexcitation, these relationships have the potential to sustain self-propagating neurodegenerative cycles that could culminate in a progressive neurodegenerative disorder such as Alzheimer's disease.

PMID:
22171672
[PubMed - as supplied by publisher]
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8.
EMBO Mol Med. 2011 Dec 14. doi: 10.1002/emmm.201100195. [Epub ahead of print]

β- but not γ-secretase proteolysis of APP causes synaptic and memory deficits in a mouse model of dementia.

Source

Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Abstract

A mutation in the BRI2/ITM2b gene causes loss of BRI2 protein leading to familial Danish dementia (FDD). BRI2 deficiency of FDD provokes an increase in amyloid-β precursor protein (APP) processing since BRI2 is an inhibitor ofAPP proteolysis, and APP mediates the synaptic/memory deficits in FDD. APP processing is linked to Alzheimer disease (AD) pathogenesis, which is consistent with a common mechanism involving toxic APP metabolites in both dementias. We show that inhibition of APP cleavage by β-secretase rescues synaptic/memory deficits in a mouse model of FDD. β-cleavage of APP yields amino-terminal-soluble APPβ (sAPPβ) and β-carboxyl-terminal fragments (β-CTF). Processing of β-CTF by γ-secretase releases Aβ, which is assumed to cause AD. However, inhibition of γ-secretase did not ameliorate synaptic/memory deficits of FDD mice. These results suggest that sAPPβ and/or β-CTF, rather than Aβ, are the toxic species causing dementia, and indicate that reducing β-cleavage of APP is an appropriate therapeutic approach to treating human dementias. Our data and the failures of anti-Aβ therapies in humans advise against targeting γ-secretase cleavage of APP and/or Aβ.

Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

PMID:
22170863
[PubMed - as supplied by publisher]
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9.
Eur J Hum Genet. 2011 Dec 14. doi: 10.1038/ejhg.2011.225. [Epub ahead of print]

A genome-wide study reveals rare CNVs exclusive to extreme phenotypes ofAlzheimer disease.

Source

1] Inserm U614, Faculté de Médecine, Rouen, France [2] CNR-MAJ, CHU Rouen, CHU Lille, CHU Pitié Salpétrière, Paris, France.

Abstract

Studying rare extreme forms of Alzheimer disease (AD) may prove to be a useful strategy in identifying new genes involved in monogenic determinism of AD. Amyloid precursor protein (APP), PSEN1, and PSEN2 mutations account for only 85% of autosomal dominant early-onset AD (ADEOAD) families. We hypothesised that rare copy number variants (CNVs) could be involved in ADEOAD families without mutations in known genes, as well as in rare sporadic young-onset AD cases. Using high-resolution array comparative genomic hybridisation, we assessed the presence of rare CNVs in 21 unrelated ADEOAD cases, having no alteration on known genes, and 12 sporadic AD cases, with an age of onset younger than 55 years. The analysis revealed the presence of 7 singleton CNVs (4 in ADEOAD and 3 in sporadic cases) absent in 1078 controls and 912 late-onset AD cases. Strikingly, 4 out of 7 rearrangements target genes (KLK6, SLC30A3, MEOX2, and FPR2) encoding proteins that are tightly related to amyloid-β peptide metabolism or signalling. Although these variants are individually rare and restricted to particular subgroups of patients, these findings support the causal role, in human pathology, of a set of genes coding for molecules suspected for a long time to modify Aβ metabolism or signalling, and for which animal or cellular models have already been developed.European Journal of Human Genetics advance online publication, 14 December 2011; doi:10.1038/ejhg.2011.225.

PMID:
22166940
[PubMed - as supplied by publisher]
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10.
Mol Med. 2011 Dec 1. doi: 10.2119/molmed.2011.00366. [Epub ahead of print]

BETA-AMYLOID CARRYING THE DUTCH MUTATION HAS DIVERSE EFFECTS ON CALPAIN-MEDIATED TOXICITY IN HIPPOCAMPAL NEURONS.

Source

Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.

Abstract

Hereditary cerebral hemorrhage with amyloidosis-Dutch type is a disorder associated with a missense mutation (E693Q) in the beta-amyloid (Aβ)-coding region of the amyloid precursor protein. This familial disease is characterized by cognitive deficits secondary to intracerebral hemorrhage and, in some cases, progressive Alzheimer disease (AD)-like dementia. Although this mutation was the first ever reported in the human APP gene, little is known about the molecular mechanisms underlying the direct toxic effects of this mutated Aβ on central neurons. In the present study, we assessed the role of calpain-mediated toxicity in such effects using an AD primary culture model system. Our results showed that Dutch mutant Aβ (E22Q) induced calpain-mediated cleavage of dynamin 1 and a significant decrease in synaptic contacts in mature hippocampal cultures. These synaptic deficits were similar to those induced by wild type Aβ. In contrast, calpain-mediated tau cleavage leading to the generation of a 17 kDa neurotoxic fragment, as well as neuronal death, were significantly reduced in E22Q Aβ-treated neurons when compared to WT Aβ-treated ones. This complex regulation of the calpain-mediated toxicity pathway by E22Q Aβ could have some bearings in the pathobiology of this familial AD form.

PMID:
22160219
[PubMed - as supplied by publisher]
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11.
Platelets. 2011 Dec 13. [Epub ahead of print]

Low-density platelet populations demonstrate low in vivo activity in sporadicAlzheimer disease.

Source

Department of Internal Medicine, The Vrinnevi Hospital , Norrköping , Sweden.

Abstract

Platelets contain a substantial quantity of amyloid-precursor protein (APP) and β-amyloid. However, despite the large importance of APP and β-amyloid to dementia, little is known about platelets in sporadic Alzheimer dementia (AD). Furthermore, platelet heterogeneity influences human pathology and has been described to affect the progression of AD. This study investigated AD platelets with respect to density diversity and in vivo activity associated with density sub-fractions. We included 39 AD patients and used, as controls, 22 elderly individuals without apparent memory disorder. A continuous Percoll™ gradient covering the density span 1.04-1.09 kg/l provided the basis to divide platelets of whole blood into density fractions (n = 16). All platelet populations were evaluated accordingly. Platelet counts were determined electronically. A flow-cytometer was put to use to measure surface-bound fibrinogen as a measure of platelet in vivo activity. Samples obtained from patients diagnosed with sporadic AD contained platelets (fractions numbers 4-16) that circulated with significantly less surface-bound fibrinogen, i.e., their platelet activation in vivo was reduced, compared with controls. In particular, highly significant differences (p < 0.001) were obtained for the six less dense platelet populations (fractions numbers 11-16) when comparing sporadic AD with controls. In contrast, the densest AD platelets in fractions numbers 1-3 did not differ significantly from control cells with respect to in vivo platelet-bound fibrinogen. It is concluded that sporadic AD is characterized by lower density platelet populations that, while circulating, exhibited reduced activation. The clinical significance of this finding is unclear but these results suggest the importance of platelet heterogeneity in dementia as a topic for further investigation.

PMID:
22150375
[PubMed - as supplied by publisher]
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12.
Int J Alzheimers Dis. 2011;2011:345614. Epub 2011 Nov 15.

Disturbed copper bioavailability in Alzheimer's disease.

Source

Institute of Chemistry and Biochemistry, Freie Universität Berlin, Thielallee 63, 14195 Berlin, Germany.

Abstract

Recent data from in vitro, animal, and human studies have shed new light on the positive roles of copper in many aspects of AD. Copper promotes the non-amyloidogenic processing of APP and thereby lowers the Aβ production in cell culture systems, and it increases lifetime and decreases soluble amyloid production in APP transgenic mice. In a clinical trial with Alzheimer patients, the decline of Aβ levels in CSF, which is a diagnostic marker, is diminished in the verum group (8 mg copper/day), indicating a beneficial effect of the copper treatment. These observations are in line with the benefit of treatment with compounds aimed at normalizing metal levels in the brain, such as PBT2. The data reviewed here demonstrate that there is an apparent disturbance in metal homeostasis in AD. More research is urgently needed to understand how this disturbance can be addressed therapeutically.

PMID:
22145082
[PubMed - in process]
PMCID: PMC3227474
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13.
J Biol Chem. 2011 Dec 5. [Epub ahead of print]

Amyloid precursor protein revisited: Neuronal-specific expression and the highly stable nature of soluble derivatives.

Source

Baylor College of Medicine, United States.

Abstract

APP processing and Aβ production plays a central role in Alzheimer disease (AD) pathogenesis. APP has been considered a ubiquitously expressed protein. In addition to Aβ, α- or β-secretase dependent cleavage of APP also generates soluble secreted APP (APPsα or APPsβ respectively). Interestingly, APPsβ has been shown to be subject to further cleavage to create an N-APP fragment which binds to the DR6 death receptor and mediates axon pruning and degeneration under trophic factor withdrawal conditions. By performing APP immunocytochemical staining, we found that, unexpectedly, many antibodies yielded non-specific staining in APP null samples. Screening of a series of antibodies allowed us to identify a rabbit monoclonal antibody Y188 that is highly specific for APP and prompted us to re-examine the expression, localization and stability of endogenous APP and APPsβ in wild-type and in APPsβ knock-in mice, respectively. In contrast to earlier reports, we found that APP is specifically expressed in neurons and its expression cannot be detected in major types of glial cells under basal or neuroinflammatory conditions. Both APPsα and APPsβ are highly stable in the central nervous system (CNS) and do not undergo further cleavage with or without trophic factor support. Our results clarify several key questions with regards to the fundamental properties of APP and offer critical cellular insights into the pathophysiology of APP.

PMID:
22144675
[PubMed - as supplied by publisher]
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14.
Neurobiol Aging. 2011 Nov 25. [Epub ahead of print]

DLB and PDD: a role for mutations in dementia and Parkinson disease genes?

Source

Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium; Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium.

Abstract

Based on the substantial overlap in clinical and pathological characteristics of dementia with Lewy bodies (DLB) and Parkinson disease with dementia (PDD) with Alzheimer disease (AD) and Parkinson disease (PD) we hypothesized that these disorders might share underlying genetic factors. The contribution of both sequence and copy number variants (CNVs) in known AD and PD genes to the genetic etiology of DLB and PDD however is currently unclear. Therefore, we performed a gene-based mutation analysis of all major AD and PD genes in 99 DLB and 75 PDD patients, including familial and sporadic forms, from Flanders, Belgium. Also, copy number variants in APP, SNCA, and PARK2 were determined. In the AD genes we detected proven pathogenic missense mutations in PSEN1 and PSEN2, and 2 novel missense variants in PSEN2 and MAPT. In the PD genes we identified 1 SNCA duplication, the LRRK2 R1441C founder mutation and 4 novel heterozygous missense variants with unknown pathogenicity. Our results suggest a contribution of established AD and PD genes to the genetic etiology of DLB and PDD though to a limited extent. They do support the hypothesis of a genetic overlap between members of the Lewy body disease spectrum, but additional genes still have to exist.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID:
22118943
[PubMed - as supplied by publisher]
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15.
Autophagy. 2011 Dec 1;7(12). [Epub ahead of print]

Macroautophagy-generated increase of lysosomal amyloid β-protein mediates oxidant-induced apoptosis of cultured neuroblastoma cells.

Source

Division of Geriatric Medicine; Department of Clinical and Experimental Medicine; IKE; Faculty of Health Sciences; Linköping University; Linköping, Sweden.

Abstract

Increasing evidence suggests the toxicity of intracellular amyloid β-protein (Aβ) to neurons, as well as the involvement of oxidative stress in Alzheimer disease (AD). Here we show that normobaric hyperoxia (exposure of cells to 40% oxygen for five days, and consequent activation of macroautophagy and accumulation of Aβ within lysosomes, induced apoptosis in differentiated SH-SY5Y neuroblastoma cells. Cells under hyperoxia showed: (1) increased numbers of autophagic vacuoles that contained amyloid precursor protein (APP) as well as Aβ monomers and oligomers, (2) increased reactive oxygen species production, and (3) enhanced apoptosis. Oxidant-induced apoptosis positively correlated with cellular Aβ production, being the highest in cells that were stably transfected with APP Swedish KM670/671NL double mutation. Inhibition of γ-secretase, prior and/or in parallel to hyperoxia, suggested that the increase of lysosomal Aβ resulted mainly from its autophagic uptake, but also from APP processing within autophagic vacuoles. The oxidative stress-mediated effects were prevented by macroautophagy inhibition using 3-methyladenine or ATG5 downregulation. Our results suggest that upregulation of macroautophagy and resulting lysosomal Aβ accumulation are essential for oxidant-induced apoptosis in cultured neuroblastoma cells and provide aditional support for the interactive role of oxidative stress and the lysosomal system in AD-related neurodegeneration.

PMID:
22108004
[PubMed - as supplied by publisher]
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16.
Dev Neurobiol. 2011 Nov 18. doi: 10.1002/dneu.22001. [Epub ahead of print]

Modulation of transient receptor potential melastatin related 7 (TRPM7) channel by presenilins.

Source

Department of Physiology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440746, South Korea.

Abstract

Presenilins (PS1 and PS2) are multi-functional proteins involved in a diverse array of molecular and cellular functions, including proteolysis, development, neurogenesis, synaptic plasticity, ion channel regulation and phospholipid metabolism. Mutations in presenilin genes are responsible for the majority of Familial Alzheimer disease (FAD). Consequently, FAD-associated mutations in genes encoding PS1 or PS2 lead to several key cellular phenotypes, including alterations in proteolysis of β-amyloid precursor protein (APP) and Ca(2+) entry. The mechanism underlying presenilin (PS)-mediated modulation of Ca(2+) entry remains to be determined. Our previous studies showed that the PS-dependent down-regulation of phosphatidylinositol-4,5-bisphosphate (PIP2) is attributable to the observed Ca(2+) deficits. In this study, we attempted to identify the ion channel that is subject to the PIP2 and PS-dependent modulation. We found that Ca(2+) or Zn(2+) entry via the transient receptor potential melastatin 7 (TRPM7) channel was attenuated by the presence of FAD-associated PS1 mutants, such as ΔE9 and L286V. TRPM7 has been implicated in Mg(2+) homeostasis and embryonic development. The intracellular delivery of PIP2 restored TRPM7-mediated Ca(2+) influx, indicating that the observed deficits in Ca(2+) entry are due to down-regulation of PIP2. Conversely, PS1 and PS2 deficiency, previously shown to up-regulate PIP2 levels, potentiated TRPM7-mediated Ca(2+) influx. PS-dependent changes in Ca(2+) influx could be neutralized by a TRPM7 channel blocker. Collectively, these results indicate that TRPM7 may underlie the Ca(2+) entry deficits observed in FAD-associated PS mutants and suggest that the normal function of PS involves regulation of TRPM7 through a PIP2-dependent mechanism. © 2011 Wiley Periodicals, Inc. Develop Neurobiol, 2011.

Copyright © 2011 Wiley Periodicals, Inc.

PMID:
22102510
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17.
J Biol Chem. 2012 Jan 6;287(2):1100-11. Epub 2011 Nov 15.

Down-regulation of the ATP-binding Cassette Transporter 2 (Abca2) Reduces Amyloid-β Production by Altering Nicastrin Maturation and Intracellular Localization.

Source

From the Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KU Leuven, 3000 Leuven, Belgium.

Abstract

Clinical, pharmacological, biochemical, and genetic evidence support the notion that alteration of cholesterol homeostasis strongly predisposes to Alzheimer disease (AD). The ATP-binding cassette transporter-2 (Abca2), which plays a role in intracellular sterol trafficking, has been genetically linked to AD. It is unclear how these two processes are related. Here we demonstrate that down-regulation of Abca2 in mammalian cells leads to decreased amyloid-β (Aβ) generation. In vitro studies revealed altered γ-secretase complex formation in Abca2 knock-out cells due to the altered levels, post-translational modification, and subcellular localization of Nicastrin. Reduced Abca2 levels in mammalian cells in vitro, in Drosophila melanogaster and in mice resulted in altered γ-secretase processing of APP, and thus Aβ generation, without affecting Notch cleavage.

PMID:
22086926
[PubMed - in process]
PMCID: PMC3256850
[Available on 2013/1/6]
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18.
J Neurosci. 2011 Nov 9;31(45):16227-40.

Morphine protects against intracellular amyloid toxicity by inducing estradiol release and upregulation of Hsp70.

Source

Laboratory of Neurobiology and State Key Laboratory of Biomembrane and Membrane Biotechnology, College of Life Sciences and College of Urban and Environmental Sciences, Peking University, Beijing 100871, China.

Abstract

Certain experimental models support morphine can play a beneficial role against damage in the neuronal system. In this study, we find morphine as well as endomorphin-1 and endomorphin-2 can protect against intracellular amyloid β (iAβ) toxicity in human and rat primary neuronal cultures and in rat brains in vivo. Morphine reverses the electrophysiological changes induced by iAβ, including current density, resting membrane potential and capacitance. Also morphine improves the spatial memory performance in rats infected by iAβ packaged virus and in APP/PS1 mice in Morris water maze tests. Morphine protection is mediated through inducing estradiol release in hippocampal neurons measured by ELISA and liquid chromatography-mass spectrometry, possibly by increasing P450 cytochrome aromatase activity. Released estradiol induces upregulation of heat shock protein 70 (Hsp70). Hsp70 protects against intracellular amyloid toxicity by rescuing proteasomal activity which is impaired by iAβ. This is the first time, to our knowledge, that induction of estradiol release in hippocampal neurons by morphine is reported. Our data may contribute to both Alzheimer'sdisease therapy and pain clinics where morphine is widely used.

PMID:
22072674
[PubMed - indexed for MEDLINE]
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19.
J Biol Chem. 2011 Dec 30;286(52):45063-72. Epub 2011 Nov 7.

Translational Repression of the Disintegrin and Metalloprotease ADAM10 by a Stable G-quadruplex Secondary Structure in Its 5'-Untranslated Region.

Source

From the Adolf Butenandt Institute, Biochemistry, Ludwig Maximilians University, 80336 Munich, Germany and.

Abstract

Anti-amyloidogenic processing of the amyloid precursor protein APP by α-secretase prevents formation of the amyloid-β peptide, which accumulates in senile plaques of Alzheimer disease patients. α-Secretase belongs to the family of a disintegrin and metalloproteases (ADAMs), and ADAM10 is the primary candidate for this anti-amyloidogenic activity. We recently demonstrated that ADAM10 translation is repressed by its 5'-UTR and that in particular the first half of ADAM10 5'-UTR is responsible for translational repression. Here, we asked whether specific sequence motifs exist in the ADAM10 5'-UTR that are able to form complex secondary structures and thus potentially inhibit ADAM10 translation. Using circular dichroism spectroscopy, we demonstrate that a G-rich region between nucleotides 66 and 94 of the ADAM10 5'-UTR forms a highly stable, intramolecular, parallel G-quadruplex secondary structure under physiological conditions. Mutation of guanines in this sequence abrogates the formation of the G-quadruplex structure. Although the G-quadruplex structure efficiently inhibits translation of a luciferase reporter in in vitro translation assays and in living cells, inhibition of G-quadruplex formation fails to do so. Moreover, expression of ADAM10 was similarly repressed by the G-quadruplex. Mutation of the G-quadruplex motif results in a significant increase of ADAM10 levels and consequently APPsα secretion. Thus, we identified a critical RNA secondary structure within the 5'-UTR, which contributes to the translational repression of ADAM10.

PMID:
22065584
[PubMed - in process]
PMCID: PMC3248004
[Available on 2012/12/30]
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20.
J Neurosci. 2011 Nov 2;31(44):15861-9.

Dynamic analysis of amyloid β-protein in behaving mice reveals opposing changes in ISF versus parenchymal Aβ during age-related plaque formation.

Source

Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.

Abstract

Growing evidence supports the hypothesis that soluble, diffusible forms of the amyloid β-peptide (Aβ) are pathogenically important in Alzheimer's disease (AD) and thus have both diagnostic and therapeutic salience. To learn more about the dynamics of soluble Aβ economy in vivo, we used microdialysis to sample the brain interstitial fluid (ISF), which contains the most soluble Aβ species in brain at steady state, in >40 wake, behaving APP transgenic mice before and during the process of Aβ plaque formation (age 3-28 months). Diffusible forms of Aβ, especially Aβ(42), declined significantly in ISF as mice underwent progressive parenchymal deposition of Aβ. Moreover, radiolabeled Aβ administered at physiological concentrations into ISF revealed a striking difference in the fate of soluble Aβ in plaque-rich (vs plaque-free) mice: it clears more rapidly from the ISF and becomes more associated with the TBS-extractable pool, suggesting that cerebral amyloid deposits can rapidly sequester soluble Aβ from the ISF. Likewise, acute γ-secretase inhibition in plaque-free mice showed a marked decline of Aβ(38), Aβ(40), and Aβ(42), whereas in plaque-rich mice, Aβ(42) declined significantly less. These results suggest that most of the Aβ(42) that populates the ISF in plaque-rich mice is derived not from new Aβ biosynthesis but rather from the large reservoir of less soluble Aβ(42) in brain parenchyma. Together, these and other findings herein illuminate the in vivo dynamics of soluble Aβ during the development of AD-type neuropathology and after γ-secretase inhibition and help explain the apparent paradox that CSF Aβ(42) levels fall as humans develop AD.

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