Intracellular copper deficiency increases amyloid-β secretion by diverse mechanisms

2008 ◽  
Vol 412 (1) ◽  
pp. 141-152 ◽  
Author(s):  
Michael A. Cater ◽  
Kelly T. McInnes ◽  
Qiao-Xin Li ◽  
Irene Volitakis ◽  
Sharon La Fontaine ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Copper Deficiency ◽  
Human Fibroblasts ◽  
Amyloid Β ◽  
Copper Accumulation ◽  
Amyloid Β Peptide ◽  
Human Neuroblastoma ◽  
Aβ Amyloid ◽  
Intracellular Copper

In Alzheimer's disease there is abnormal brain copper distribution, with accumulation of copper in amyloid plaques and a deficiency of copper in neighbouring cells. Excess copper inhibits Aβ (amyloid β-peptide) production, but the effects of deficiency have not yet been determined. We therefore studied the effects of modulating intracellular copper levels on the processing of APP (amyloid precursor protein) and the production of Aβ. Human fibroblasts genetically disposed to copper accumulation secreted higher levels of sAPP (soluble APP ectodomain)α into their medium, whereas fibroblasts genetically manipulated to be profoundly copper deficient secreted predominantly sAPPβ and produced more amyloidogenic β-cleaved APP C-termini (C99). The level of Aβ secreted from copper-deficient fibroblasts was however regulated and limited by α-secretase cleavage. APP can be processed by both α- and β-secretase, as copper-deficient fibroblasts secreted sAPPβ exclusively, but produced primarily α-cleaved APP C-terminal fragments (C83). Copper deficiency also markedly reduced the steady-state level of APP mRNA whereas the APP protein level remained constant, indicating that copper deficiency may accelerate APP translation. Copper deficiency in human neuroblastoma cells significantly increased the level of Aβ secretion, but did not affect the cleavage of APP. Therefore copper deficiency markedly alters APP metabolism and can elevate Aβ secretion by either influencing APP cleavage or by inhibiting its degradation, with the mechanism dependent on cell type. Overall our results suggest that correcting brain copper imbalance represents a relevant therapeutic target for Alzheimer's disease.

scholarly journals Copper Depletion Down-regulates Expression of the Alzheimer's Disease Amyloid-β Precursor Protein Gene

2004 ◽  
Vol 279 (19) ◽  
pp. 20378-20386 ◽  
Author(s):  
Shayne A. Bellingham ◽  
Debomoy K. Lahiri ◽  
Bryan Maloney ◽  
Sharon La Fontaine ◽  
Gerd Multhaup ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Fibroblasts ◽  
Amyloid Β ◽  
Copper Homeostasis ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
Copper Depletion ◽  
Intracellular Copper

Alzheimer's disease is characterized by the accumulation of amyloid-β peptide, which is cleaved from the amyloid-β precursor protein (APP). Reduction in levels of the potentially toxic amyloid-β has emerged as one of the most important therapeutic goals in Alzheimer's disease. Key targets for this goal are factors that affect the regulation of theAPPgene. Recentin vivoandin vitrostudies have illustrated the importance of copper in Alzheimer's disease neuropathogenesis and suggested a role for APP and amyloid-β in copper homeostasis. We hypothesized that metals and in particular copper might alterAPPgene expression. To test the hypothesis, we utilized human fibroblasts overexpressing the Menkes protein (MNK), a major mammalian copper efflux protein.MNKdeletion fibroblasts have high intracellular copper, whereas MNK overexpressing fibroblasts have severely depleted intracellular copper. We demonstrate that copper depletion significantly reduced APP protein levels and down-regulatedAPPgene expression. Furthermore,APPpromoter deletion constructs identified the copper-regulatory region between -490 and +104 of theAPPgene promoter in both basal MNK overexpressing cells and in copper-chelatedMNKdeletion cells. Overall these data support the hypothesis that copper can regulateAPPexpression and further support a role for APP to function in copper homeostasis. Copper-regulatedAPPexpression may also provide a potential therapeutic target in Alzheimer's disease.

Amyloid β-peptide and Alzheimer's disease

2014 ◽  
Vol 56 ◽  
pp. 99-110 ◽  
Author(s):  
David Allsop ◽  
Jennifer Mayes
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaques ◽  
Strong Support ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Amyloid Cascade Hypothesis ◽  
Sequence Of Events ◽  
Aβ Amyloid ◽  
Amyloid Cascade

One of the hallmarks of AD (Alzheimer's disease) is the formation of senile plaques in the brain, which contain fibrils composed of Aβ (amyloid β-peptide). According to the ‘amyloid cascade’ hypothesis, the aggregation of Aβ initiates a sequence of events leading to the formation of neurofibrillary tangles, neurodegeneration, and on to the main symptom of dementia. However, emphasis has now shifted away from fibrillar forms of Aβ and towards smaller and more soluble ‘oligomers’ as the main culprit in AD. The present chapter commences with a brief introduction to the disease and its current treatment, and then focuses on the formation of Aβ from the APP (amyloid precursor protein), the genetics of early-onset AD, which has provided strong support for the amyloid cascade hypothesis, and then on the development of new drugs aimed at reducing the load of cerebral Aβ, which is still the main hope for providing a more effective treatment for AD in the future.

Synaptic memory mechanisms: Alzheimer's disease amyloid β-peptide-induced dysfunction

2007 ◽  
Vol 35 (5) ◽  
pp. 1219-1223 ◽  
Author(s):  
M.J. Rowan ◽  
I. Klyubin ◽  
Q. Wang ◽  
N.W. Hu ◽  
R. Anwyl
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Synaptic Plasticity ◽  
Nitrosative Stress ◽  
Amyloid Β ◽  
Long Term Potentiation ◽  
Amyloid Β Peptide ◽  
Aβ Oligomers ◽  
Aβ Amyloid

There is growing evidence that mild cognitive impairment in early AD (Alzheimer's disease) may be due to synaptic dysfunction caused by the accumulation of non-fibrillar, oligomeric Aβ (amyloid β-peptide), long before widespread synaptic loss and neurodegeneration occurs. Soluble Aβ oligomers can rapidly disrupt synaptic memory mechanisms at extremely low concentrations via stress-activated kinases and oxidative/nitrosative stress mediators. Here, we summarize experiments that investigated whether certain putative receptors for Aβ, the αv integrin extracellular cell matrix-binding protein and the cytokine TNFα (tumour necrosis factor α) type-1 death receptor mediate Aβ oligomer-induced inhibition of LTP (long-term potentiation). Ligands that neutralize TNFα or genetic knockout of TNF-R1s (type-1 TNFα receptors) prevented Aβ-triggered inhibition of LTP in hippocampal slices. Similarly, antibodies to αv-containing integrins abrogated LTP block by Aβ. Protection against the synaptic plasticity-disruptive effects of soluble Aβ was also achieved using systemically administered small molecules targeting these mechanisms in vivo. Taken together, this research lends support to therapeutic trials of drugs antagonizing synaptic plasticity-disrupting actions of Aβ oligomers in preclinical AD.

The proteins BACE1 and BACE2 and β-secretase activity in normal and Alzheimer's disease brain

2007 ◽  
Vol 35 (3) ◽  
pp. 574-576 ◽  
Author(s):  
J.H. Stockley ◽  
C. O'Neill
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Protein Levels ◽  
Rate Limiting Step ◽  
Secretase Activity ◽  
Aβ Amyloid ◽  
Ad Alzheimer’S Disease ◽  
And Function

The insidious progression of AD (Alzheimer's disease) is believed to be linked closely to the production, accumulation and aggregation of the ∼4.5 kDa protein fragment called Aβ (amyloid β-peptide). Aβ is produced by sequential cleavage of the amyloid precursor protein by two enzymes referred to as β- and γ-secretase. β-Secretase is of central importance, as it catalyses the rate-limiting step in the production of Aβ and was identified 7 years ago as BACE1 (β-site APP-cleaving enzyme 1). Soon afterwards, its homologue BACE2 was discovered, and both proteins represent a new subclass of the aspartyl protease family. Studies examining the regulation and function of β-secretase in the normal and AD brain are central to the understanding of excessive production of Aβ in AD, and in targeting and normalizing this β-secretase process if it has gone awry in the disease. Several reports indicate this, showing increased β-secretase activity in AD, with recent findings by our group showing changes in β-secretase enzyme kinetics in AD brain caused by an increased Vmax. This article gives a brief review of studies which have examined BACE1 protein levels and β-secretase activity in control and AD brain, considering further the expression of BACE2 in the human brain.

scholarly journals Mitochondrial β-amyloid in Alzheimer's disease

2011 ◽  
Vol 39 (4) ◽  
pp. 868-873 ◽  
Author(s):  
Eva Borger ◽  
Laura Aitken ◽  
Kirsty E.A. Muirhead ◽  
Zoe E. Allen ◽  
James A. Ainge ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Transgenic Animals ◽  
Transgenic Animal ◽  
Major Effect ◽  
Amyloid Β Peptide ◽  
Toxic Response ◽  
Intracellular Location ◽  
Aβ Amyloid

It is well established that the intracellular accumulation of Aβ (amyloid β-peptide) is associated with AD (Alzheimer's disease) and that this accumulation is toxic to neurons. The precise mechanism by which this toxicity occurs is not well understood; however, identifying the causes of this toxicity is an essential step towards developing treatments for AD. One intracellular location where the accumulation of Aβ can have a major effect is within mitochondria, where mitochondrial proteins have been identified that act as binding sites for Aβ, and when binding occurs, a toxic response results. At one of these identified sites, an enzyme known as ABAD (amyloid-binding alcohol dehydrogenase), we have identified changes in gene expression in the brain cortex, following Aβ accumulation within mitochondria. Specifically, we have identified two proteins that are up-regulated not only in the brains of transgenic animal models of AD but also in those of human sufferers. The increased expression of these proteins demonstrates the complex and counteracting pathways that are activated in AD. Previous studies have identified approximate contact sites between ABAD and Aβ; on basis of these observations, we have shown that by using a modified peptide approach it is possible to reverse the expression of these two proteins in living transgenic animals and also to recover mitochondrial and behavioural deficits. This indicates that the ABAD–Aβ interaction is potentially an interesting target for therapeutic intervention. To explore this further we used a fluorescing substrate mimic to measure the activity of ABAD within living cells, and in addition we have identified chemical fragments that bind to ABAD, using a thermal shift assay.

Protein–protein interactions in the assembly and subcellular trafficking of the BACE (β-site amyloid precursor protein-cleaving enzyme) complex of Alzheimer's disease

2007 ◽  
Vol 35 (5) ◽  
pp. 974-979 ◽  
Author(s):  
R.B. Parsons ◽  
B.M. Austen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Protein Interactions ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
Aβ Amyloid ◽  
Ad Alzheimer’S Disease

The correct assembly of the BACE (β-site amyloid precursor protein-cleaving enzyme or β-secretase) complex and its subsequent trafficking to cellular compartments where it associates with the APP (amyloid precursor protein) is essential for the production of Aβ (amyloid β-peptide), the protein whose aggregation into senile plaques is thought to be responsible for the pathogenesis of AD (Alzheimer's disease). These processes rely upon both transient and permanent BACE–protein interactions. This review will discuss what is currently known about these BACE–protein interactions and how they may reveal novel therapeutic targets for the treatment of AD.

Pathways linking Aβ and tau pathologies

2010 ◽  
Vol 38 (4) ◽  
pp. 993-995 ◽  
Author(s):  
Frank M. LaFerla
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurological Disorders ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Convincing Evidence ◽  
Amyloid Β Peptide ◽  
Tau Pathology ◽  
Aβ Amyloid ◽  
Cellular Compartments

Aβ (amyloid β-peptide) and tau are the main proteins that misfold and accumulate in amyloid plaques and NFTs (neurofibrillary tangles) of Alzheimer's disease and other neurological disorders. Historically, because plaques and NFTs accumulate in diverse cellular compartments, i.e. mainly extracellularly for plaques and intracellularly for NFTs, it was long presumed that the constituent proteins formed these lesions via unrelated pathways. Animal and cell studies over the last decade, however, have provided convincing evidence to show that Aβ can facilitate the development of tau pathology by altering several cell-dependent and -independent mechanisms. In the present article, results are reviewed from several laboratories that show that modulating Aβ pathology can directly affect the development of tau pathology, which has significant implications for the treatment of Alzheimer's disease.

Impairment of the activity of the plasma membrane Ca2+-ATPase in Alzheimer's disease

2011 ◽  
Vol 39 (3) ◽  
pp. 819-822 ◽  
Author(s):  
Ana M. Mata ◽  
María Berrocal ◽  
M. Rosario Sepúlveda
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Plasma Membrane ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Inhibitory Effect ◽  
Amyloid Β Peptide ◽  
Aβ Amyloid

AD (Alzheimer's disease) is an age-associated neurodegenerative disorder where the accumulation of neurotoxic Aβ (amyloid β-peptide) in senile plaques is a typical feature. Recent studies point out a relationship between Aβ neurotoxicity and Ca2+ dyshomoeostasis, but the molecular mechanisms involved are still under discussion. The PMCAs (plasma membrane Ca2+-ATPases) are a multi-isoform family of proteins highly expressed in brain that is implicated in the maintenance of low intraneural Ca2+ concentration. Therefore the malfunction of this pump may also be responsible for Ca2+ homoeostasis failure in AD. We have found that the Ca2+-dependence of PMCA activity is affected in human brains diagnosed with AD, being related to the enrichment of Aβ. The peptide produces an inhibitory effect on the activity of PMCA which is isoform-specific, with the greatest inhibition of PMCA4. Besides, cholesterol blocked the inhibitory effect of Aβ, which is consistent with the lack of any Aβ effect on PMCA4 found in cholesterol-enriched lipid rafts isolated from pig brain. These observations suggest that PMCAs are a functional component of the machinery that leads to Ca2+ dysregulation in AD and propose cholesterol enrichment in rafts as a protector of the Aβ-mediated inhibition on PMCA.

Disease modifying strategies for the treatment of Alzheimer's disease targeted at modulating levels of the β-amyloid peptide

2005 ◽  
Vol 33 (4) ◽  
pp. 553-558 ◽  
Author(s):  
M.N. Pangalos ◽  
S.J. Jacobsen ◽  
P.H. Reinhart
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Cell Death ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Proteolytic Processing ◽  
Amyloid Peptide ◽  
Amyloid Β Peptide ◽  
Aβ Amyloid ◽  
Disease Modifying

AD (Alzheimer's disease) is characterized neuropathologically by the presence of amyloid plaques, neurofibrillary tangles and profound grey matter loss. The ‘amyloid’ hypothesis postulates that the toxic Aβ (amyloid β) peptide, enzymatically derived from the proteolytic processing of a larger protein called APP (amyloid precursor protein), is one of the principal causative factors of neuronal cell death in the brains of AD patients. As such, methods for lowering Aβ levels in the brain are of significant interest with regard to identifying novel disease modifying therapies for the treatment of AD. In this review, we will review a variety of approaches and mechanisms capable of modulating levels of Aβ.

Inhibition of Aβ(1–40) fibril formation by cyclophilins

2016 ◽  
Vol 473 (10) ◽  
pp. 1355-1368 ◽  
Author(s):  
Marten Villmow ◽  
Monika Baumann ◽  
Miroslav Malesevic ◽  
Rolf Sachs ◽  
Gerd Hause ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Fibril Formation ◽  
Water Soluble ◽  
Main Process ◽  
Amyloid Β Peptide ◽  
Cyclophilin D ◽  
Aβ Amyloid

Cyclophilins interact directly with the Alzheimer's disease peptide Aβ (amyloid β-peptide) and are therefore involved in the early stages of Alzheimer's disease. Aβ binding to CypD (cyclophilin D) induces dysfunction of human mitochondria. We found that both CypD and CypA suppress in vitro fibril formation of Aβ(1–40) at substoichiometric concentrations when present early in the aggregation process. The prototypic inhibitor CsA (cyclosporin A) of both cyclophilins as well as the new water-soluble MM258 derivative prevented this suppression. A SPOT peptide array approach and NMR titration experiments confirmed binding of Aβ(1–40) to the catalytic site of CypD mainly via residues Lys16–Glu22. The peptide Aβ(16–20) representing this section showed submicromolar IC50 values for the peptidyl prolyl cis–trans isomerase activity of CypD and CypA and low-micromolar KD values in ITC experiments. Chemical cross-linking and NMR-detected hydrogen–deuterium exchange experiments revealed a shift in the populations of small Aβ(1–40) oligomers towards the monomeric species, which we investigated in the present study as being the main process of prevention of Aβ fibril formation by cyclophilins.

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