Chemistry Reference
In-Depth Information
1.3.2.1
b
-Amyloid Peptides
Alzheimer's disease (AD) is a progressive brain-degenerative disease among elderly peo-
ple and is the most common cause of dementia, which eventually leads to the loss of
ability to perform daily routines. An estimate of about 2.4-4.5 million Americans have
this disease, showing first symptom after age 60 in most cases [180]. Although the etiol-
ogy of this disease has not been fully established, evidence for possible causes has been
hypothesized and demonstrated. The aggregation of b-amyloid peptide (Ab) in the brain
as plaques and fibrils have been hypothesized to be associated with the pathogenesis of
AD [181], which has gained further support from the fact that Ab plaques are toxic to
neurons and some rat models [181-183] and the overexpression of Ab in familial AD and
Down's syndrome results in early onset of the disease [184]. Nevertheless, the role of Ab
coagulation in AD has still been challenged [185]. The linkage between the structure and
reactivity of Ab and AD must be further clarified to provide possible prevention and treat-
ment of this disease.
The Ab peptides are generated by cleaving the ubiquitous amyloid precursor protein
(APP) by a, b, and g secretases, wherein Ab(1-40/42) fragments (with sequence DAEFR
HDSGY
10
EVHHQ KLVFF
20
AEDVG SNKGA
30
IIGLM VGGVV
40
IA) are generated
by secretases b and g while Ab(1-16) is released by secretases a and b [186]. Abs have
several potential metal-binding residues, including Asp, His, Tyr, and Glu frequently
found as ligands in metalloproteins [187]. Growing evidence has pointed out the involve-
ment of metal ions, including Fe
2þ/3þ
,Cu
2þ
, and Zn
2þ
, in the conformational changes of
Ab into fibrils and plaques and the role of metallo-Ab in causing oxidative stress in the
brain of AD patients [188]. The variant His
13
Gln revealed the importance of this His
for metal binding and the formation of Ab plaques [188g]. Likewise, mouse Ab with
His
13
!
Argismuchlessapttoformaggregatesin the presence of metal ions [188a].
Redox-active Cu- and Fe-Ab complexes may exhibit neurotoxicity via the generation of
reactive oxygen species (ROS), which can cause damage to cell membranes, proteins,
nucleic acids, and other biomolecules and lead to cell death [189]. Moreover, the signifi-
cance of the soluble forms of Ab in the pathogenesis of AD has also been proposed and
verified [190].
The structure and metal binding of Ab and the chemistry associated with metallo-Ab
have emerged from studies using different physical methods [188,191]. For example: the
morphology of Ab fibrils was revealed by electron microscope; [192] Ab fibers and the
hydrophobic C-terminal fragments of the peptide were shown by X-ray diffraction [193]
and solid-state NMR techniques [194] to adopt a b-sheet structure (Figure 1.15a), whereas
Ab in micelles [195] and an intermediate during Ab fibrillogenesis [196] have a-helical
structures (Figure 1.15b); an extended structure of Ab upon binding to insulin-degrading
enzyme was shown by X-ray crystallography (Figure 1.15c) [197]; the structure of the Zn-
Ab complex was determined by NMR to show a coordinated Asp11 residue along with
three His residues (twoN
d
-andoneN
e
-coordinated; Figure 1.15d) [198]; the structure of
Co
2þ
-Ab was determined on the basis of hyperfine-shifted His ring protons and molecular
mechanics calculations to show three N
e
-coordinatedHisresiduesaswellasthepresenceof
an extended H-bonding framework (Figure 1.15e) [199]; and damage to cellular components
such as membranes by metallo-Ab-mediated ROS was determined on the basis of the
reaction products [200]. From these studies, the conformational change of Ab peptides upon
!
Search WWH ::
Custom Search