Friday, January 6, 2012

beta amyloid precursor protein | What is beta amyloid precursor protein|Papers on beta amyloid precursor protein|Research on beta amyloid precurso


1.
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-amyloidplaques 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]
2.
Neurochem Res. 2012 Jan 5. [Epub ahead of print]

Restraint Stress in Rats Alters Gene Transcription and Protein Translation in the Hippocampus.

Source

Department of Psychiatry, Alzheimer's Disease Research Centre, University of Szeged, Kálvária sgt. 57, 6701, Szeged, Hungary, santha.petra@gmail.com.

Abstract

Stress is a relatively new and emerging risk factor for Alzheimer's disease (AD). Severe stress can alter brain characteristics such as neuronal plasticity, due to changes in the metabolism of cytoskeletal proteins. In this study, male Wistar rats were exposed to restraint stress (RS) for 5 h daily for different time periods. At the end of the exposure periods, the amounts of β-actin, cofilin, amyloid precursor protein (APP) and mitogen-activated protein kinase 1 (MAPK-1) RNAs and proteins were investigated. The mRNA expressions of β-actin, cofilin and MAPK-1 followed U-shaped time course. Acute (3 days) and chronic (21 days) RS caused a fourfold and tenfold increases, respectively, in hippocampal β-actin mRNA expression. In the case of cofilin mRNA expression, elevations were detected in the hippocampus on days 3, 7 and 21. The APP mRNA level was increased on day 21. On protein level, chronic stress elevated the levels of β-actin, cofilin and APP in the hippocampus. These results suggest that stress causes the induction of some genes and proteins that are also elevated in AD selectively in the hippocampal region of the rat brain.

PMID:
22219132
[PubMed - as supplied by publisher]
3.
J Alzheimers Dis. 2012 Jan 3. [Epub ahead of print]

Down-Regulation of Amyloid-β Through AMPK Activation by Inhibitors of GSK-3β in SH-SY5Y and SH-SY5Y-AβPP695 Cells.

Source

Department of Neurology, The Affiliated Hospital of Guangdong Medical College, Zhanjiang, China Department of Urology, The University of Kansas Medical Center, Kansas City, KS, USA.

Abstract

Glycogen synthase kinase 3β (GSK-3β) plays a critical role in the pathogenesis of Alzheimer's disease (AD), implicating amyloid-β (Aβ) production, neurofibrillary tangle formation, and neuronal apoptosis. The activation of 5' AMP-activated protein kinase (AMPK) has been linked to aberrant processing of amyloidprotein precursor (AβPP), and AMPK signaling controls Aβ metabolism. It is possible that GSK-3β regulated the activation of the AMPK pathway. To test this hypothesis, the influence of GSK-3β on the expression of AβPP cleavage enzyme (BACE), Aβ, and AMPK in the SH-SY5Y and AβPP695 cells line through three inhibitors of GSK-3β was analyzed. Expression of Aβ, AMPK, and pAMPK172 was measured by Western blot, and BACE was tested by Western blot and RT-PCR. This study demonstrated that suppression of GSK-3β activity, through specific inhibitors, dramatically down-regulated Aβ generation in human SH-SY5Y and SH-SY5Y-AβPP695 cells by enhancing AMPK activity to down-regulate Aβ. These results suggest GSK-3β inhibitors may be promising agents in the prevention and treatment of AD.

PMID:
22214783
[PubMed - as supplied by publisher]
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4.
J Biomed Sci. 2012 Jan 3;19(1):2. [Epub ahead of print]

siRNA against presenilin 1 (PS1) down regulates amyloid beta 42 production in IMR-32 cells.

Abstract

ABSTRACT:

BACKGROUND:

One of the pathological hallmarks of Alzheimer's disease (AD) is the deposition of the ~4 kDa amyloidbeta protein (Abeta) within lesions known as senile plaques. Abeta is also deposited in the walls of cerebral blood vessels in many cases of AD. A substantial proportion of the Abeta that accumulates in the AD brain is deposited asAmyloid, which is highly insoluble, proteinaceous material with a beta-pleated-sheet conformation and deposited extracellularly in the form of 5-10 nm wide straight fibrils. As gamma-secretase catalyzes the final cleavage that releases the Abeta42 or 40 from amyloid beta -protein precursor (APP), therefore, it is a potential therapeutic target for the treatment of AD. gamma-Secretase cleavage is performed by a high molecular weight protein complex containing presenilins (PSs), nicastrin, Aph-1 and Pen-2. Previous studies have demonstrated that the presenilins (PS1 and PS2) are critical components of a large enzyme complex that performs gamma-secretase cleavage.

METHODS:

In this study we used RNA interference (RNAi) technology to examine the effects of small-interfering RNA (siRNA) against PS1 on expression levels of PS1 and Abeta42 in IMR-32 Cells using RTPCR, western blotting and immunofluorescence techniques.

RESULTS:

The results of the present study showed down regulation of PS1 and Abeta42 in IMR32 cells transfected with siRNA against PS1.

CONCLUSION:

Our results substantiate the concept that PS1 is involved in gamma-secretase activity and provides the rationale for therapeutic strategies aimed at influencing Abeta42 production.

PMID:
22214483
[PubMed - as supplied by publisher]
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5.
Cytometry A. 2011 Dec 28. doi: 10.1002/cyto.a.22009. [Epub ahead of print]

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]
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6.
Mol Psychiatry. 2012 Jan 3. doi: 10.1038/mp.2011.168. [Epub ahead of print]

Amine oxidase activity of β-amyloid precursor protein modulates systemic and local catecholamine levels.

Source

1] The Mental Health Research Institute, The University of Melbourne, Parkville, VIC, Australia [2] Center for Neuroscience, The University of Melbourne, Parkville, VIC, Australia.

Abstract

The catecholamines dopamine (DA), norepinephrine (NE) and epinephrine (E) are neurotransmitters and hormones that mediate stress responses in tissues and plasma. The expression of β-amyloid precursor protein (APP) is responsive to stress and is high in tissues rich in catecholamines. We recently reported that APP is a ferroxidase, subsuming, in neurons and other cells, the iron-export activity that ceruloplasmin mediates in glia. Here we report that, like ceruloplasmin, APP also oxidizes synthetic amines and catecholamines catalytically (K(m) NE=0.27 mM), through a site encompassing its ferroxidase motif and selectively inhibited by zinc. Accordingly, APP knockout mice have significantly higher levels of DA, NE and E in brain, plasma and select tissues. Consistent with this, these animals have increased resting heart rate and systolic blood pressure as well as suppressed prolactin and lymphocyte levels. These findings support a role for APP in extracellular catecholaminergic clearance.Molecular Psychiatry advance online publication, 3 January 2012; doi:10.1038/mp.2011.168.

PMID:
22212595
[PubMed - as supplied by publisher]
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7.
Neurobiol Aging. 2011 Dec 31. [Epub ahead of print]

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]
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8.
J Neurochem. 2011 Dec 30. doi: 10.1111/j.1471-4159.2011.07642.x. [Epub ahead of print]

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]
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9.
Curr Pharm Des. 2012 Jan 1. [Epub ahead of print]

Resveratrol, a neuroprotective supplement for Alzheimer's disease.

Source

School of Traditional Chinese Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. feili@northwestern.edu.

Abstract

The polyphenolic compound resveratrol (3,4',5-trihydroxystilbene) is a naturally occurring phytochemical which has been found in more than 70 plant species, including herbs and human food products such as grapes, berries, and peanuts. Resveratrol was first isolated in 1940; however, little attention was paid to it until its benefits in coronary heart disease were studied in 1992. Since then, increasing evidence has indicated that resveratrol may be useful in treating cardiovascular diseases, cancers, pain, inflammation, tissue injury, and in reducing the risk of neurodegenerative disorders, especially Alzheimer's disease (AD). AD is characterized by a progressive dementia, and is one of the most common neurodegenerative disorders in the elderly. It has been reported that resveratrol exhibits neuroprotective benefits in animal models of AD. Resveratrol promotes the non-amyloidogenic cleavage of the amyloid precursor protein, enhances clearance of amyloid beta-peptides, and reduces neuronal damage. Despite the effort spent trying to understand the mechanisms by which resveratrol functions, the research work in this field is still incomplete. Many concerns such as bioavailability, biotransformation, synergism with other dietary factors, and risks inherent to its possible pro-oxidant activities still need to be addressed. This review summarizes and discusses the neuroprotective effects of resveratrol on AD, and their potential mechanisms.

PMID:
22211686
[PubMed - as supplied by publisher]
10.
Environ Toxicol Pharmacol. 2011 Dec 10;33(2):135-140. [Epub ahead of print]

The profile of β-amyloid precursor protein expression of rats induced by aluminum.

Source

Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China.

Abstract

The environmental agent aluminum has been extensively investigated for a potential relationship with amyloid precursorprotein (APP) expression. Despite many investigations, there is at present no definite proof from which to draw a conclusion. Since APP is an integral membrane protein expressed in different tissues and capable of fluxes across the blood-brain barrier (BBB), which may ultimately affect APP level in brain, it is necessary to assess the expression profile among vital body organs. The present study compared aluminum oxide and aluminum chloride injected rats with control rats (saline treated) to observe if aluminum affected APP expression patterns in different organs by immunohistochemistry (IHC). The expression of APP was observed in the brain of aluminum chloride treated rats and in the liver of aluminum oxide injected group. Results of double IHC staining showed that it is Kupffer cells, which are located in liver sinus and expressed APP after aluminum oxide treatment. Oxidative stress is suggested as the potential pathway that aluminum chloride exert effects in brain. These results suggest that different aluminum compounds may impact the expression of APP in brain and liver tissues. The mechanism that aluminum induced liver APP expression still needs further investigation.

Copyright © 2011 Elsevier B.V. All rights reserved.

PMID:
22209725
[PubMed - as supplied by publisher]
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11.
J Nutr Biochem. 2011 Dec 29. [Epub ahead of print]

Trans fatty acids enhance amyloidogenic processing of the Alzheimer amyloidprecursor 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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12.
Neurobiol Aging. 2011 Dec 27. [Epub ahead of print]

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.

PMID:
22206846
[PubMed - as supplied by publisher]
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13.
Biochem Biophys Res Commun. 2011 Dec 20. [Epub ahead of print]

The Nogo receptor 2 is a novel substrate of Fbs1.

Source

Neurobiochemistry - Biocenter, Innsbruck Medical University, Fritz-Preglstraße 3, 6020 Innsbruck, Austria.

Abstract

Members of the Nogo66 receptor family (NgR) are closely associated with nerve growth inhibition and plasticity in the CNS. All three members, NgR1, NgR2 and NgR3, are GPI anchored and highly glycosylated proteins. The binding and signaling properties of NgR1 are well described, but largely unknown for NgR2. At present the only known ligands are myelin associated glycoprotein (MAG) and amyloid beta precursor protein (APP). Despite the requirement of co-receptors for signaling no other binding partner has been uncovered. To learn more about the interactome of NgR2 we performed pull down experiments and were able to identify F-box protein that recognizes sugar chain 1 (Fbs1) as binding partner. We confirmed this finding with co-immunoprecipitations and in vitro binding assays and showed that the binding is mediated by the substrate recognition domain of Fbs1. As a substrate recognition protein of the SCF complex, Fbs1 binding leads to polyubiquitination and finally degradation of its substrates. This is the first time a member of the Nogo receptor family has been connected with an intracellular degradation pathway, which has not only implications for its production, but also for amyloid deposition in Alzheimer's disease.

Copyright © 2011. Published by Elsevier Inc.

PMID:
22206664
[PubMed - as supplied by publisher]
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14.
Neurodegener Dis. 2011 Dec 23. [Epub ahead of print]

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 proteinand 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.

PMID:
22205103
[PubMed - as supplied by publisher]
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15.
Neurodegener Dis. 2011 Dec 23. [Epub ahead of print]

p53, a Pivotal Effector of a Functional Cross-Talk Linking Presenilins and Pen-2.

Source

Institut de Pharmacologie Moléculaire et Cellulaire et Institut de NeuroMédecine Moléculaire, Equipe Labellisée Fondation pour la Recherche Médicale, Valbonne, France.

Abstract

The γ-secretase is a multiprotein complex responsible for the ultimate cut yielding amyloid-β peptides and their N-terminal truncated species. This complex is composed of at least four distinct entities, namely presenilin-1 (PS1) or PS2, anterior pharynx defective-1, presenilin enhancer-2 (Pen-2) and nicastrin. Very few studies examined the transcriptional regulation of this complex, and more precisely, whether some of the members functionally interact. Here, we summarize our previous data documenting the fact that Pen-2 controls cell death in a p53-dependent manner and our recent demonstration of a pivotal role of p53 as a regulator of Pen-2 transcription. As PS trigger amyloid precursorprotein intracellular domain-dependent regulation of p53, our studies delineate a feedback control mechanism by which PS and Pen-2 functionally interact in a p53-dependent manner.

Copyright © 2011 S. Karger AG, Basel.

PMID:
22205087
[PubMed - as supplied by publisher]
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16.
J Alzheimers Dis. 2011 Dec 27. [Epub ahead of print]

Fibrillar Amyloid-β1-42 Modifies Actin Organization Affecting the Cofilin Phosphorylation State: A Role for Rac1/cdc42 Effector Proteins and the Slingshot Phosphatase.

Source

Laboratory of Cellular and Molecular Neurosciences, University of Chile and International Center for Biomedicine (ICC), Santiago, Chile.

Abstract

The neuronal cytoskeleton regulates numerous processes that occur in normal homeostasis. Under pathological conditions such as those of Alzheimer's disease (AD), major alterations in cytoskeleton organization have been observed and changes in both microtubules and actin filaments have been reported. Many neurodegenerative consequences of AD are linked to the production and accumulation of amyloid peptides (Aβ) and their oligomers, produced from the internal cleavage of the amyloidprotein precursor. We previously reported that fibrillar Aβ1-42 (fAβ) treatment of hippocampal neurons induced an increase in Rac1 and Cdc42 activities linking fAβ effects with changes in actin dynamics. Here we show fAβ-induces increased activity of PAK1 and cyclin-dependent kinase 5, and that p21-activated kinase (PAK1) activation targets the LIMK1-cofilin signaling pathway. Increased cofilin dephosphorylation under conditions of enhanced LIM-Kinase 1 (LIMK1) activity suggests that fAβ co-stimulates bifurcating pathways impacting cofilin phosphorylation. Overexpression of slingshot (SSH) prevents the augment of F-actin induced by fAβ after 24 h, suggesting that fAβ-induced changes in actin assembly involve both LIMK1 and SSH. These results suggest that fAb may alter the PAK1/LIMK1/cofilin axis and therefore actin organization in AD.

PMID:
22204905
[PubMed - as supplied by publisher]
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17.
Mol Neurodegener. 2011 Dec 28;6(1):88. [Epub ahead of print]

The Alzheimer's beta-secretase enzyme BACE1 is required for accurate axon guidance of olfactory sensory neurons and normal glomerulus formation in the olfactory bulb.

Abstract

ABSTRACT:

BACKGROUND:

The beta-secretase, beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), is a prime therapeutic target for lowering cerebral beta-amyloid (Abeta) levels in Alzheimer's disease (AD). Clinical development of BACE1 inhibitors is being intensely pursued. However, little is known about the physiological functions of BACE1, and the possibility exists that BACE1 inhibition may cause mechanism-based side effects. Indeed, BACE1-/- mice exhibit a complex neurological phenotype. Interestingly, BACE1 co-localizes with presynaptic neuronal markers, indicating a role in axons and/or terminals. Moreover, recent studies suggest axon guidance molecules are potential BACE1 substrates. Here, we used a genetic approach to investigate the function of BACE1 in axon guidance of olfactory sensory neurons (OSNs), a well-studied model of axon targeting in vivo.

RESULTS:

We bred BACE1-/- mice with gene-targeted mice in which GFP is expressed from the loci of two odorant-receptors (ORs), MOR23 and M72, and olfactory marker protein (OMP) to produce offspring that were heterozygous for MOR23-GFP, M72-GFP, or OMP-GFP and were either BACE1+/+ or BACE1-/-. BACE1-/- mice had olfactory bulbs (OBs) that were smaller and weighed less than OBs of BACE1+/+ mice. In wild-type mice, BACE1 was present in OSN axon terminals in OB glomeruli. In whole-mount preparations and tissue sections, many OB glomeruli from OMP-GFP; BACE1-/- mice were malformed compared to wild-type glomeruli. MOR23-GFP; BACE1-/- mice had an irregular MOR23 glomerulus that was innervated by randomly oriented, poorly fasciculated OSN axons compared to BACE1+/+ mice. Most importantly, M72-GFP; BACE1-/- mice exhibited M72 OSN axons that were mis-targeted to ectopic glomeruli, indicating impaired axon guidance in BACE1-/- mice.

CONCLUSIONS:

Our results demonstrate that BACE1 is required for the accurate targeting of OSN axons and the proper formation of glomeruli in the OB, suggesting a role for BACE1 in axon guidance. OSNs continually undergo regeneration and hence require ongoing axon guidance. Neurogenesis and the regeneration of neurons and axons occur in other adult populations of peripheral and central neurons that also require axon guidance throughout life. Therefore, BACE1 inhibitors under development for the treatment of AD may potentially cause axon targeting defects in these neuronal populations as well.

PMID:
22204380
[PubMed - as supplied by publisher]
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18.
Mol Neurodegener. 2011 Dec 28;6(1):87. [Epub ahead of print]

Transgenic neuronal overexpression reveals that stringently regulated p23 expression is critical for coordinated movement in mice.

Abstract

ABSTRACT:

BACKGROUND:

p23 belongs to the highly conserved p24 family of type I transmembrane proteins, which participate in bidirectional protein transport between the endoplasmic reticulum and Golgi apparatus. Mammalian p23 has been shown to interact with gamma-secretase complex, and modulate secretory trafficking as well as intramembranous processing of amyloid precursor protein in cultured cells. Negative modulation of beta-amyloid production by p23 in cultured cell lines suggested that elevation of p23 expression in neurons might mitigate cerebral amyloid burden.

RESULTS:

We generated several lines of transgenic mice expressing human p23 in neurons under the control of Thy-1.2 promoter. We found that even a 50% increase in p23 levels in the central nervous system of mice causes post-natal growth retardation, severe neurological problems characterized by tremors and seizure, ataxia, and uncoordinated movements, and premature death. The severity of the phenotype closely correlated with the level of p23 overexpression in multiple transgenic lines. While the number and general morphology of neurons in Hup23 mice appeared to be normal throughout the brain, abnormal non-Golgi p23 localization was observed in a subset of neurons with high transgene expression in brainstem. Moreover, detailed immunofluorescence analysis revealed marked proliferation of astrocytes, activation of microglia, and thinning of myelinated bundles in brainstem of Hup23 mice.

CONCLUSIONS:

These results demonstrate that proper level of p23 expression is critical for neuronal function, and perturbing p23 function by overexpression initiates a cascade of cellular reactions in brainstem that leads to severe motor deficits and other neurological problems, which culminate in premature death. The neurological phenotype observed in Hup23 mice highlights significant adverse effects associated with manipulating neuronal expression of p23, a previously described negative modulator of gamma-secretase activity and beta-amyloid production. Moreover, our report has broader relevance to molecular mechanisms in several neurodegenerative diseases as it highlights the inherent vulnerability of the early secretory pathway mechanisms that ensure proteostasis in neurons.

PMID:
22204304
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19.
Neurochem Int. 2011 Dec 19. [Epub ahead of print]

Promotion of β-amyloid production by C-reactive protein and its implications in the early pathogenesis of Alzheimer's disease.

Source

Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.

Abstract

C-reactive protein (CRP) and β-amyloid protein (Aβ) are involved in the development of Alzheimer's disease (AD). However, the relationship between CRP and Aβ production is unclear. In vitro and in vivo experiments were performed to investigate the association of CRP with Aβ production. Using the rat adrenal pheochromocytoma cell line (PC12 cells) to mimic neurons, cytotoxicity was evaluated by cell viability and supernatant lactate dehydrogenase (LDH) activity. The levels of amyloid precursor protein (APP), beta-site APP cleaving enzyme (BACE-1), and presenilins (PS-1 and PS-2) were investigated using real-time polymerase chain reaction and Western blotting analysis. Aβ1-42 was measured by enzyme-linked immunosorbent assay. The relevance of CRP and Aβ as well as potential mechanisms were studied using APP/PS1 transgenic (Tg) mice. Treatment with 0.5-4.0μM CRP for 48h decreased cell viability and increased LDH leakage in PC12 cells. Incubation with CRP at a sub-toxic concentration of 0.2μM increased the mRNA levels of APP, BACE-1, PS-1, and PS-2, as well as Aβ1-42 production. CRP inhibitor reversed the CRP-induced upregulations of the mRNA levels of APP, BACE-1, PS-1, and PS-2, and the protein levels of APP, BACE-1, PS-1, and Aβ1-42, but did not reversed Aβ1-42 cytotoxicity. The cerebral levels of CRP and Aβ1-42 in APP/PS1 Tg mice were positively correlated, accompanied with the elevated mRNA expressions of serum amyloid P component (SAP), complement component 1q (C1q), and tumor necrosis factor-α (TNF-α). These results suggest that CRP cytotoxicity is associated with Aβ formation and Aβ-related markers expressions; CRP and Aβ were relevant in early-stage AD; CRP may be an important trigger in AD pathogenesis.

Copyright © 2011. Published by Elsevier Ltd.

PMID:
22202667
[PubMed - as supplied by publisher]
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20.
Front Biosci (Schol Ed). 2012 Jan 1;4:1126-50.

Alpha, beta-and gamma-secretases in alzheimer's disease.

Source

Universita degli Studi di Milano, Department of Pharmacological Sciences, Via Balzaretti, 9, Milano, Italy.

Abstract

Generation of Amyloid peptide (Abeta) is at the beginning of a cascade that leads to Alzheimer's disease. Currenty, the mechanisms of Abeta generation and Abeta prevention are subject of intensive research. Amyloid precursor protein(APP), as well as beta- and gamma-secretases are the principal players involved in Abeta production, while alpha-secretase cleavage on APP prevents Abeta deposition. Inhibitors or modulators that target beta- and gamma-secretases as well as alpha-secretase activators are promising candidates for treatment of Alzheimer's disease. A deep knowledge of the secretases is required to develop disease modifying drugs that target them. The most challenging quest is to translate the growing knowledge about the cell biology of secretases and their mechanisms of action into effective therapeutics. Here, we review the main features of the secretases.

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