Inhibitors of protein aggregation and toxicity

2009 ◽  
Vol 37 (4) ◽  
pp. 692-696 ◽  
Author(s):  
Hozefa Amijee ◽  
Jill Madine ◽  
David A. Middleton ◽  
Andrew J. Doig
Keyword(s):  
Amyloid Β ◽  
Long Term Potentiation ◽  
Amyloid Β Peptide ◽  
Recognition Element ◽  
Self Recognition ◽  
Term Potentiation ◽  
Starting Point ◽  
Aβ Amyloid ◽  
Aggregation Inhibitors ◽  
Ad Alzheimer’S Disease

The aggregation of numerous peptides or proteins has been linked to the onset of disease, including Aβ (amyloid β-peptide) in AD (Alzheimer's disease), asyn (α-synuclein) in Parkinson's disease and amylin in Type 2 diabetes. Diverse amyloidogenic proteins can often be cut down to an SRE (self-recognition element) of as few as five residues that retains the ability to aggregate. SREs can be used as a starting point for aggregation inhibitors. In particular, N-methylated SREs can bind to a target on one side, but have hydrogen-bonding blocked on their methylated face, interfering with further assembly. We applied this strategy to develop Aβ toxicity inhibitors. Our compounds, and a range of compounds from the literature, were compared under the same conditions, using biophysical and toxicity assays. Two N-methylated D-peptide inhibitors with unnatural side chains were the most effective and can reverse Aβ-induced inhibition of LTP (long-term potentiation) at concentrations as low as 10 nM. An SRE in asyn (VAQKTV) was identified using solid-state NMR. When VAQKTV was N-methylated, it was able to disrupt asyn aggregation. N-methylated derivatives of the SRE of amylin are also able to inhibit amylin aggregation.

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.

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.

Drug targets for amyloidosis

2010 ◽  
Vol 38 (2) ◽  
pp. 466-470 ◽  
Author(s):  
Simon E. Kolstoe ◽  
Steve P. Wood
Keyword(s):  
Protein Misfolding ◽  
Drug Targets ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Transthyretin Amyloidosis ◽  
Amyloid Deposits ◽  
Aβ Amyloid ◽  
Amyloidogenic Protein ◽  
Cross Links ◽  
Ad Alzheimer’S Disease

The amyloid hypothesis indicates that protein misfolding is at the root of many neurodegenerative disorders. Small molecules targeting the formation, clearance, aggregation to toxic oligomers or SOD (superoxide dismutase)-like activities of Aβ (amyloid β-peptide) 1–42 have provided encouraging candidates for AD (Alzheimer's disease) medicines in animal models, although none have yet proved to be effective in human trials. We have been investigating approaches to treat systemic amyloidoses, conditions that show common features with some CNS (central nervous system) disorders. For TTR (transthyretin) amyloidosis, we are seeking small molecule compounds that stabilize the amyloidogenic protein and either prevent its structural transition to the crossed β fibres deposited in diseased tissues, or promote its clearance from circulation. Effective stabilizer compounds that simultaneously bind to both thyroxine-binding sites have been developed. A more generic approach involves targeting the plasma glycoprotein SAP (serum amyloid P component). This protein recognizes the misfolded polypeptide structures of amyloid deposits wherever they occur, and acts as a powerful anti-opsonin. We have developed a bivalent drug called CPHPC {(R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylic acid} that cross-links pairs of pentameric SAP molecules and causes their rapid elimination from the circulation. This strategy raises the prospect of encouraging natural mechanisms to clear amyloid and recent work suggests that this approach extends to the CNS.

Novel heparan sulphate analogues: inhibition of β-secretase cleavage of amyloid precursor protein

2005 ◽  
Vol 33 (5) ◽  
pp. 1116-1118 ◽  
Author(s):  
S.J. Patey ◽  
E.A. Yates ◽  
J.E. Turnbull
Keyword(s):  
Amyloid Precursor Protein ◽  
Heparan Sulphate ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
Neuritic Plaques ◽  
Rate Limiting Step ◽  
Aβ Amyloid ◽  
Ad Alzheimer’S Disease

The role of HS (heparan sulphate) in the pathology of AD (Alzheimer's disease) is multifaceted. HS and other glycosaminoglycans have been widely reported to be associated with neuritic plaques. HS has also been shown to promote the aggregation of Aβ (amyloid β-peptide), the proteinaceous component of neuritic plaques. Recently, we described a novel and contrasting role for HS in the pathology of AD: HS can inhibit the formation of Aβ, by directly interacting with the protease BACE1 (β-site amyloid precursor protein cleaving enzyme 1; β-secretase 1), that cleaves the amyloid precursor protein and is the rate limiting step in the generation of Aβ. Here, we review the current roles of HS and the potential for HS-derivatives in the treatment of AD.

scholarly journals Amyloid-β Peptide Is Needed for cGMP-Induced Long-Term Potentiation and Memory

2017 ◽  
Vol 37 (29) ◽  
pp. 6926-6937 ◽  
Author(s):  
Agostino Palmeri ◽  
Roberta Ricciarelli ◽  
Walter Gulisano ◽  
Daniela Rivera ◽  
Claudia Rebosio ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Long Term Potentiation ◽  
Amyloid Β Peptide ◽  
Term Potentiation

Ca2+ enhances Aβ polymerization rate and fibrillar stability in a dynamic manner

2013 ◽  
Vol 450 (1) ◽  
pp. 189-197 ◽  
Author(s):  
Kristoffer Brännström ◽  
Anders Öhman ◽  
Malin Lindhagen-Persson ◽  
Anders Olofsson
Keyword(s):  
Self Assembly ◽  
Molecular Mechanisms ◽  
Amyloid Β ◽  
Mechanistic Explanation ◽  
Elongation Rate ◽  
Polymerization Rate ◽  
Amyloid Β Peptide ◽  
Aβ Amyloid ◽  
Ad Alzheimer’S Disease

Identifying factors that affect the self-assembly of Aβ (amyloid-β peptide) is of utmost importance in the quest to understand the molecular mechanisms causing AD (Alzheimer's disease). Ca2+ has previously been shown to accelerate both Aβ fibril nucleation and maturation, and dysregulated Ca2+ homoeostasis frequently correlates with development of AD. The mechanisms regarding Ca2+ binding, as well as its effect on fibril kinetics, are not fully understood. Using a polymerization assay we show that Ca2+ in a dynamic and reversible manner enhances both the elongation rate and fibrillar stability, where specifically the ‘dock and lock’ phase mechanism is enhanced. Through NMR analysis we found that Ca2+ affects the fibrillar architecture. In addition, and unexpectedly, we found that Ca2+ does not bind the free Aβ monomer. This implies that Ca2+ binding requires an architecture adopted by assembled peptides, and consequently is mediated through intermolecular interactions between adjacent peptides. This gives a mechanistic explanation to the enhancing effect on fibril maturation and indicates structural similarities between prefibrillar structures and mature amyloid. Taken together we show how Ca2+ levels affect the delicate equilibrium between the monomeric and assembled Aβ and how fluctuations in vivo may contribute to development and progression of the disease.

scholarly journals Surprising toxicity and assembly behaviour of amyloid β-protein oxidized to sulfone

2010 ◽  
Vol 433 (2) ◽  
pp. 323-332 ◽  
Author(s):  
Panchanan Maiti ◽  
Roberto Piacentini ◽  
Cristian Ripoli ◽  
Claudio Grassi ◽  
Gal Bitan
Keyword(s):  
Amino Acids ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Amyloid Β Protein ◽  
Wild Type ◽  
Neuronal Viability ◽  
Β Protein ◽  
Aβ Amyloid ◽  
Assembly Kinetics ◽  
Ad Alzheimer’S Disease

Aβ (amyloid β-peptide) is believed to cause AD (Alzheimer's disease). Aβ42 (Aβ comprising 42 amino acids) is substantially more neurotoxic than Aβ40 (Aβ comprising 40 amino acids), and this increased toxicity correlates with the existence of unique Aβ42 oligomers. Met35 oxidation to sulfoxide or sulfone eliminates the differences in early oligomerization between Aβ40 and Aβ42. Met35 oxidation to sulfoxide has been reported to decrease Aβ assembly kinetics and neurotoxicity, whereas oxidation to sulfone has rarely been studied. Based on these data, we expected that oxidation of Aβ to sulfone would also decrease its toxicity and assembly kinetics. To test this hypothesis, we compared systematically the effect of the wild-type, sulfoxide and sulfone forms of Aβ40 and Aβ42 on neuronal viability, dendritic spine morphology and macroscopic Ca2+ currents in primary neurons, and correlated the data with assembly kinetics. Surprisingly, we found that, in contrast with Aβ-sulfoxide, Aβ-sulfone was as toxic and aggregated as fast, as wild-type Aβ. Thus, although Aβ-sulfone is similar to Aβ-sulfoxide in its dipole moment and oligomer size distribution, it behaves similarly to wild-type Aβ in its aggregation kinetics and neurotoxicity. These surprising data decouple the toxicity of oxidized Aβ from its initial oligomerization, and suggest that our current understanding of the effect of methionine oxidation in Aβ is limited.

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