Human cystatin C (HCC) is a family 2 cystatin inhibitor of papain-like
(C1) and legumain-related (C13) cysteine proteases. In pathophysiological
processes, the nature of which is not understood, HCC is codeposited in
the amyloid plaques of Alzheimer’s disease or Down’s syndrome.
The eﬀect of the extracellular chaperone, clusterin, on amyloid ﬁbril formation by lipid-free human apolipoprotein C-II (apoC-II) was investigated. Sub-stoichiometric levels of clusterin, derived from either plasma or semen, potently inhibit amyloid formation by apoC-II. Inhibition is dependent on apoC-II concentration, with more eﬀective inhibition by clusterin observed at lower concentrations of apoC-II. The average sedimentation coeﬃcient of apoC-II ﬁbrils formed from apoC-II (0.3 mgÆmL)1) is reduced by coincubation with clusterin (10 lgÆmL)1). ...
Alzheimer’s disease (AD) is an age-related, progressive degenerative dis-order that is characterized by synapse and neuron loss in the brain and the
accumulation of protein-containing deposits (referred to as ‘senile plaques’)
and neurofibrillary tangles. Insoluble amyloid b-peptide (Ab) fibrillar
aggregates found in extracellular plaques have long been thought to cause
the neurodegenerative cascades of AD.
The prion-forming domain comprising residues 218–289 of the fungal prion
HET-s forms infectious amyloid fibrils at physiological pH. Because a
high-resolution molecular model for the structure of these fibrils exists, it
constitutes an attractive system with which to study the mechanism of amy-loid assembly.
Amyloid-b(Ab) aggregation and amyloid formation are key pathological
features of Alzheimer’s disease, and are considered to be two of the major
contributing factors to neurodegeneration and dementia. Identification of
small molecule inhibitors that are orally available, have low toxicity and
high central nervous system bioavailability is one approach to the potential
development of a disease-modifying treatment for Alzheimer’s disease.
Alzheimer’s disease and Creutzfeldt–Jakob disease are the best-known
examples of a group of diseases known as the amyloidoses. They are char-acterized by the extracellular deposition of toxic, insoluble amyloid fibrils.
Knowledge of the structure of these fibrils is essential for understanding
the process of pathology of the amyloidoses and for the rational design of
drugs to inhibit or reverse amyloid formation.
Phospholipids are known to influence fibril formation of amyloid beta (Ab)
peptide. Here, we show that lysophosphatidylcholine (LPC), a polar phos-pholipid, enhances Ab(1-42) fibril formation, by decreasing the lag time
and the critical peptide concentration required for fibril formation, and
increasing the fibril elongation rate.
Cleavage of the amyloid precursor protein (APP) within the amyloid-beta
(Ab) sequence by the a-secretase prevents the formation of toxic Abpep-tides. It has been shown that the disintegrin-metalloproteinases ADAM10
and TACE (ADAM17) act asa-secretases and stimulate the generation of
a soluble neuroprotective fragment of APP, APPsa.
The phenomenon of the transformation of proteins into amyloid-ﬁbrils is of interest, ﬁrstly, because it is closely connected to the so-called conformational diseases, many of which are hitherto incurable, and secondly, because it remains to be explained in physical terms (energetically and structurally). The process leads to ﬁbrous aggregates in the form of extracellular amyloid plaques, neuro-ﬁbrillary tangles and other intracytoplasmic or intranuclear inclusions.
Conformational diseases constitute a group of heterologous disorders in
which a constituent host protein undergoes changes in conformation, lead-ing to aggregation and deposition. To understand the molecular mecha-nisms of the process of amyloid fibril formation, numerousin vitro and
in vivo studies, including model and pathologically relevant proteins, have
Human stefin B, from the family of cystatins, is used as a model amyloido-genic protein in studies of the mechanism of amyloid fibril formation and
related cytotoxicity. Interaction of the protein’s prefibrillar oligo-mers⁄aggregates with predominantly acidic phospholipid membranes is
known to correlate with cellular toxicity.
The role of amino acid side chain oxidation in the formation of amyloid
assemblies has been investigated. Chemical oxidation of amino acid side
chains has been used as a facile method of introducing mutations on pro-tein structures. Oxidation promotes changes within tertiary contacts that
enable identification of residues and interactions critical in stabilizing pro-tein structures.
Several proteins that interact with cell surface glycolipids share a common
fold with a solvent-exposed aromatic residue that stacks onto a sugar ring of
the glycolipid (CH–pstacking interaction). Stacking interactions between
aromatic residues (p–pstacking) also play a pivotal role in the assembly pro-cess, including many cases of amyloid fibril formation.
Tuyển tập các báo cáo nghiên cứu về y học được đăng trên tạp chí y học quốc tế cung cấp cho các bạn kiến thức về ngành y đề tài: Research In silico modeling of the specific inhibitory potential of thiophene-2,3-dihydro-1,5-benzothiazepine against BChE in the formation of β-amyloid plaques associated with Alzheimer's disease...
The formation and structure of proinsulin C-peptide oligomers has been
investigated by PAGE, NMR spectroscopy and dynamic light scattering.
The results obtained show that C-peptide forms oligomers of different
sizes, and that their formation and size distribution is altered by salt and
divalent metal ions, which indicates that the aggregation process is medi-ated by electrostatic interactions.
Human transthyretin (hTTR) is one of several proteins known to cause
amyloid disease. Conformational changes in its native structure result in
aggregation of the protein, leading to insoluble amyloid fibrils. The trans-thyretin (TTR)-related proteins comprise a protein family of 5-hydroxyiso-urate hydrolases with structural similarity to TTR.
Acetylcholinesterase is an enzyme associated with senile plaques. Biochemi-cal studies have indicated that acetylcholinesterase induces amyloid fibril
formation by interaction throughout the peripherical anionic site of the
enzyme forming highly toxic acetylcholinesterase–amyloid-bpeptide (Ab)
The formation of amyloid fibrils is associated with various human medical
disorders of unrelated origin. Recent research indicates that self-assembled
amyloid fibrils are also involved in physiological processes in several micro-organisms. Yet, the molecular basis for the recognition and self-assembly
processes mediating the formation of such structures from their soluble
protein precursors is not fully understood.
Recently, a novel plaque-associated protein, collagenous Alzheimer amy-loid plaque component (CLAC), was identified in brains from patients with
Alzheimer’s disease. CLAC is derived from a type II transmembrane colla-gen precursor protein, termed CLAC-P (collagen XXV). The biological
function and the contribution of CLAC to the pathogenesis of Alzheimer’s
disease and plaque formation are unknown.
The conformational conversion of prion protein (PrP) from a native con-formation to the amyloid form is a hallmark of transmissible spongiform
encephalopathies. Conversion is usually monitored by fluorescent dyes,
which bind generic amyloids and are less suited for living cell imaging.