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.

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.

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.

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.

GULP1 is a novel APP-interacting protein that alters APP processing

2011 ◽  
Vol 436 (3) ◽  
pp. 631-639 ◽  
Author(s):  
Candy Yan Hao ◽  
Michael S. Perkinton ◽  
William Wai-Lun Chan ◽  
Ho Yin Edwin Chan ◽  
Christopher C. J. Miller ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Adaptor Protein ◽  
Amyloid Β Peptide ◽  
Interacting Proteins ◽  
Interacting Protein ◽  
App Processing ◽  
Aβ Amyloid ◽  
Full Complement ◽  
Ad Alzheimer’S Disease ◽  
Aβ Production

Altered production of Aβ (amyloid-β peptide), derived from the proteolytic cleavage of APP (amyloid precursor protein), is believed to be central to the pathogenesis of AD (Alzheimer's disease). Accumulating evidence reveals that APPc (APP C-terminal domain)-interacting proteins can influence APP processing. There is also evidence to suggest that APPc-interacting proteins work co-operatively and competitively to maintain normal APP functions and processing. Hence, identification of the full complement of APPc-interacting proteins is an important step for improving our understanding of APP processing. Using the yeast two-hybrid system, in the present study we identified GULP1 (engulfment adaptor protein 1) as a novel APPc-interacting protein. We found that the GULP1–APP interaction is mediated by the NPTY motif of APP and the GULP1 PTB (phosphotyrosine-binding) domain. Confocal microscopy revealed that a proportion of APP and GULP1 co-localized in neurons. In an APP–GAL4 reporter assay, we demonstrated that GULP1 altered the processing of APP. Moreover, overexpression of GULP1 enhanced the generation of APP CTFs (C-terminal fragments) and Aβ, whereas knockdown of GULP1 suppressed APP CTFs and Aβ production. The results of the present study reveal that GULP1 is a novel APP/APPc-interacting protein that influences APP processing and Aβ production.

Roles of apolipoprotein E4 (ApoE4) in the pathogenesis of Alzheimer's disease: lessons from ApoE mouse models

2011 ◽  
Vol 39 (4) ◽  
pp. 924-932 ◽  
Author(s):  
Yadong Huang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Apolipoprotein E4 ◽  
Apoe Isoforms ◽  
Aβ Amyloid ◽  
Ad Alzheimer’S Disease ◽  
Apoe Mouse

ApoE4 (apolipoprotein E4) is the major known genetic risk factor for AD (Alzheimer's disease). In most clinical studies, apoE4 carriers account for 65–80% of all AD cases, highlighting the importance of apoE4 in AD pathogenesis. Emerging data suggest that apoE4, with its multiple cellular origins and multiple structural and biophysical properties, contributes to AD in multiple ways either independently or in combination with other factors, such as Aβ (amyloid β-peptide) and tau. Many apoE mouse models have been established to study the mechanisms underlying the pathogenic actions of apoE4. These include transgenic mice expressing different apoE isoforms in neurons or astrocytes, those expressing neurotoxic apoE4 fragments in neurons and human apoE isoform knock-in mice. Since apoE is expressed in different types of cells, including astrocytes and neurons, and in brains under diverse physiological and/or pathophysiological conditions, these apoE mouse models provide unique tools to study the cellular source-dependent roles of apoE isoforms in neurobiology and in the pathogenesis of AD. They also provide useful tools for discovery and development of drugs targeting apoE4's detrimental effects.

Presenilins: how much more than γ-secretase?!

2010 ◽  
Vol 38 (6) ◽  
pp. 1474-1478 ◽  
Author(s):  
Katrijn Coen ◽  
Wim Annaert
Keyword(s):  
Cell Signalling ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Catalytic Activities ◽  
Gradual Loss ◽  
Disease Aetiology ◽  
Aβ Amyloid ◽  
Presenilin 2 ◽  
Ad Alzheimer’S Disease ◽  
Membrane Components

AD (Alzheimer's disease) is a neurodegenerative disease characterized by a gradual loss of neurons and the accumulation of neurotoxic Aβ (amyloid β-peptide) and hyperphosphorylated tau. The discovery of mutations in three genes, PSEN1 (presenilin 1), PSEN2 (presenilin 2) and APP (amyloid precursor protein), in patients with FAD (familial AD) has made an important contribution towards an understanding of the disease aetiology; however, a complete molecular mechanism is still lacking. Both presenilins belong to the γ-secretase complex, and serve as the catalytic entity needed for the final cleavage of APP into Aβ. PSEN only functions within the γ-secretase complex through intra- and inter-molecular interactions with three other membrane components, including nicastrin, Aph-1 (anterior pharynx defective-1) and Pen-2 (PSEN enhancer-2). However, although the list of γ-secretase substrates is still expanding, other non-catalytic activities of presenilins are also increasing the complexity behind its molecular contribution towards AD. These γ-secretase-independent roles are so far mainly attributed to PSEN1, including the transport of membrane proteins, cell adhesion, ER (endoplasmic reticulum) Ca2+ regulation and cell signalling. In the present minireview, we discuss the current understanding of the γ-secretase-independent roles of PSENs and their possible implications in respect of AD.

Intraneuronal Aβ as a trigger for neuron loss: can this be translated into human pathology?

2011 ◽  
Vol 39 (4) ◽  
pp. 857-861 ◽  
Author(s):  
Thomas A. Bayer ◽  
Oliver Wirths
Keyword(s):  
Passive Immunization ◽  
Amyloid Β ◽  
Model Systems ◽  
Special Importance ◽  
Amyloid Β Peptide ◽  
Human Pathology ◽  
Aβ Amyloid ◽  
Ad Alzheimer’S Disease ◽  
5Xfad Mice ◽  
Intraneuronal Aβ

In the present review, we summarize the current achievements of modelling early intraneuronal Aβ (amyloid β-peptide) accumulation in transgenic mice with the resulting pathological consequences. Of special importance will be to discuss recent developments and the translation of the results to AD (Alzheimer's disease). N-terminally truncated AβpE3 (Aβ starting with pyroglutamate at position 3) represents a major fraction of all Aβ peptides in the brain of AD patients. Recently, we generated a novel mAb (monoclonal antibody), 9D5, that selectively recognizes oligomeric assemblies of AβpE3 and demonstrated the potential involvement of oligomeric AβpE3in vivo using transgenic mouse models as well as human brains from sporadic and familial AD cases. 9D5 showed an unusual staining pattern with almost non-detectable plaques in sporadic AD patients and non-demented controls. Interestingly, in sporadic and familial AD cases prominent intraneuronal staining was observed. Moreover, passive immunization of 5XFAD mice with 9D5 significantly reduced overall Aβ levels and stabilized behavioural deficits. In summary, we have demonstrated that intraneuronal Aβ is a valid risk factor in model systems and AD patients. This feature of AD pathology was successful in identifying novel low-molecular-mass oligomeric Aβ-specific antibodies for diagnosis and therapy.

Metal-dependent generation of reactive oxygen species from amyloid proteins implicated in neurodegenerative disease

2008 ◽  
Vol 36 (6) ◽  
pp. 1293-1298 ◽  
Author(s):  
David Allsop ◽  
Jennifer Mayes ◽  
Susan Moore ◽  
Atef Masad ◽  
Brian J. Tabner
Keyword(s):  
Protein Misfolding ◽  
Cultured Cells ◽  
Amyloid Β ◽  
Transition Metal Ions ◽  
Transmissible Spongiform Encephalopathies ◽  
Amyloid Β Peptide ◽  
Spongiform Encephalopathies ◽  
Fenton Chemistry ◽  
Redox Active ◽  
Aβ Amyloid

Using a method based on ESR spectroscopy and spin-trapping, we have shown that Aβ (amyloid β-peptide) (implicated in Alzheimer's disease), α-synuclein (implicated in Parkinson's disease), ABri (British dementia peptide) (responsible for familial British dementia), certain toxic fragments of the prion protein (implicated in the transmissible spongiform encephalopathies) and the amylin peptide (found in the pancreas in Type 2 diabetes mellitus) all have the common ability to generate H2O2in vitro. Numerous controls (reverse, scrambled and non-toxic peptides) lacked this property. We have also noted a positive correlation between the ability of the various proteins tested to generate H2O2 and their toxic effects on cultured cells. In the case of Aβ and ABri, we have shown that H2O2 is generated as a short burst during the early stages of aggregation and is associated with the presence of protofibrils or oligomers, rather than mature fibrils. H2O2 is readily converted into the aggressive hydroxyl radical by Fenton chemistry, and this extremely reactive radical could be responsible for much of the oxidative damage seen in all of the above disorders. We suggest that the formation of a redox-active complex involving the relevant amyloidogenic protein and certain transition-metal ions could play an important role in the pathogenesis of several different protein misfolding disorders.

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