Implication of Novel Biochemical Property of β-Amyloid

Elbaum, Danek; Brzyska, Maria; Bacia, A; Alkon, Daniel L.

doi:10.1006/bbrc.1999.2024

Cited by 10 publications

(10 citation statements)

References 34 publications

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“…Our findings suggest a correlation between the secondary structure of Abeta and its ability to decompose compounds containing ester bonds. This study confirms and extends our previous studies concerning the hydrolytic properties of Abeta [8,9]. For the first time we have characterized the hydrolytic ability of Abeta towards a series of hydrocarbonaceous esters, indicating the most eagerly decomposed substrates, dependent on basic environmental factors like pH, temperature, peptide concentration and polarity of solvent.…”

Section: Discussionsupporting

confidence: 89%

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Discrete conformational changes as regulators of the hydrolytic properties of beta‐amyloid (1–40)

et al. 2006

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Beta‐amyloid (1–40) (Abeta), the main component of senile plaques seen in the brains of Alzheimer's disease patients, was found to be toxic both as fibrils and smaller soluble globular aggregates. The hydrolytic properties of Abeta, a new biochemical activity described previously [Brzyska M, Bacia A & Elbaum D (2001) Eur J Biochem268, 3443–3454], may contribute to its overall toxicity. In this study, the hydrolysis of fluorescein ester series was studied under predetermined conditions affecting Abeta hydrophobicity and conformation. Reaction products of the most effectively decomposed ester (dibutyrate) were characterized using HPLC and ESI‐MS. Hydrophobicity of Abeta, as measured by bis‐8‐anilinonaphthalene fluorescence, correlated with its hydrolytic abilities. FTIR and CD data analysis showed a relationship between enhanced hydrolytic abilities and Abeta structure. Seriously limited hydrolysis caused by higher peptide concentrations is consistent with monomeric/dimeric Abeta species participation in the process, confirmed by thioflavine T binding. Inhibition of hydrolysis was caused by β‐sheet breaker peptide (LPFFD), indicating that the Abeta central hydrophobic cluster (amino acids 17–21) participates in the process. The reported Abeta properties suggest that small conformational alterations of the peptide structure may have a pronounced effect on its functions and biological activity.

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Section: Discussionsupporting

confidence: 89%

“…Reverse structure Abeta , shorter fragments of the peptide (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) and two unrelated peptides (bradykinin and bombesin) did not cause hydrolysis of fluorescein dibutyrate (supplementary Fig. S1).…”

Section: Resultsmentioning

confidence: 99%

Discrete conformational changes as regulators of the hydrolytic properties of beta‐amyloid (1–40)

et al. 2006

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“…3). These data are consistent with previous studies suggesting that beta-amyloid-mediated hydrolysis is Ser sensitive and His, Asp/Glu also related to the activity [49].…”

Section: Hydrolytic Activities Of Aβ42supporting

confidence: 93%

“…Amino acid substitution studies indicate that the hydrophobic residues at position 17-20 are crucial for the amyloidogenic properties, with the very hydrophobic carboxy-terminal residues 29-42 corresponding to the transmembrane domain of Aβ42 [30,43]. We suggested the proteolytic activity of Aβ42 and identified essential amino acid residues and further investigated effects of bioessential metal ions for the activity [22,49].…”

Section: Hydrolytic Activities Of Aβ42mentioning

confidence: 97%

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Hydrolytic Activity of Amyloid-beta and its Inhibition with Short Peptides

Matsunaga¹,

Yamada

2005

CMCCNSA

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The main component of the amyloid plaque is insoluble Aβ1-42 (Aβ42), which adopts a structure rich in antiparallel β-pleated sheets. Recently, increasing awareness of Aβ intermediates as molten-globule states has paralleled insight into the biological activities of the Aβ conformer. The molten-globule state of Aβ42 displays a less ordered, metastable conformation that is stabilized by the formation of fibrils. The molten-globule state of the protein has many biological properties and understanding the mechanisms of its formation is an important step in devising a therapeutic strategy for Alzheimer's disease. There have been many studies of the biological properties of Aβ42 such as self-aggregation, binding to other proteins such as apolipoprotein E, cytotoxicity for neuronal cells, vasoconstriction, oxidative activity with superoxide-mediated singlet-oxygen intermediate and proteolytic activity against casein. Recent studies demonstrated that α-1 anti-chymotrypsin, a member of the serine protease inhibitor (serpin) family is also involved in the amyloid plaque. In this review, we focused on the serine protease-like activity of Aβ42 for casein substrate and the effect of bio-essential metal ions for the activity and also suggest its inhibition with Aβ42 derivatives; Aβ15-22 (QKLVFFAE) which is a potential fragment to prevent Aβ self-aggregation. Consequently, we suggest that the short peptides of this kind may be of use in the therapy of Alzheimer's disease.

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Alzheimer's Disease: Search for Therapeutics

Rzeszotarski

2003

Burger's Medicinal Chemistry and Drug Discovery

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Over the next 50 years the incidence of Alzheimer's disease (AD) in the United States is expected to triple from about 420,000 new cases in 1999 to 1.32 million per year. Assuming no successful intervention, the prevalence of AD could be expected to rise over the next 50 years by a factor of about 3.7–8.94 million, with the range of 4.55–15.81 million in the United States alone. With the exception of early‐onset familial AD (FAD) the disease is age correlated and its incidence grows exponentially with age. In part, because of their increased longevity, women represent and will continue to represent the majority (68% in 1997) of the affected population. If one adds the year 2000 U.S. census figures to the population of the European Union (EU‐15) and Japan, the prevalence of AD in “the major pharmaceutical markets” for that year could be estimated as close to 8.7 million. The as yet uncertain etiology of AD precluded the attempts to prevent its onset. Cholesterol, immune response, and oxidation damage appear to precede the deposition of amyloid β‐peptides (Aβ) and formation of senile (neuritic) plaques and intracellular neurofibrillary tangles. This is why the epidemiology and in vitro studies fail to point to right therapies. The statins, antioxidants, anti‐inflammatory agents, estrogens, or testosterone may belong to preventive measures but may fail as therapeutics. At present, no agent is available to arrest, delay, or reverse the progress of the disease.

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Implication of Novel Biochemical Property of β-Amyloid

Cited by 10 publications

References 34 publications

Discrete conformational changes as regulators of the hydrolytic properties of beta‐amyloid (1–40)

Discrete conformational changes as regulators of the hydrolytic properties of beta‐amyloid (1–40)

Hydrolytic Activity of Amyloid-beta and its Inhibition with Short Peptides

Alzheimer's Disease: Search for Therapeutics

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