REACTIVE SPECIES - Oxidation of Amino Acids, Peptides, and Proteins: Kinetics and Mechanism - page 5

roles of reactive species in common neurodegenerative diseases, Alzheimers
disease (AD) and Parkinson's disease (PD), as well as in aging, are summa-
rized below.

1.1.1.1 Alzheimers Disease. AD was first discovered in 1907 and is an irre-
versible disease, which causes unusual behavior, memory loss, personality
changes, and a decline in the ability to concentrate [28]. AD directly affects
∼10% of humans by age 65 and ∼50% by age 85 [28, 29]. Two major hypotheses
have been proposed to explain AD. The first suggests that an abnormal pro-
cessing of the amyloid precursor protein (APP) takes place during the neuro-
degeneration, which results in generation, aggregation, and deposition of the
Aβ peptide [30]. This process may facilitate neurofibrillary tangle (NFT)
peptide formation and, consequently, cell death (see Table 1.2), and is classified
as an amyloid cascade hypothesis. This hypothesis is reasonably supported by
genetic studies [31-33]. APP encodes the Aβ peptide, while the protein genes,
PS1 and PS2, encode transmembrane proteins. The second hypothesis suggests
cytoskeletal changes take place during neurodegeneration, in which hyper-
phosphorylation and aggregation of tau processes contribute to the activation
of cell death [34]. The amyloid cascade hypothesis has been investigated exten-
sively [28, 35-38]. Recently, mass spectrometry (MS) has been applied in vitro
and in vivo to learn the role of the Aβ peptide in AD [39]. Studies include
elucidating the structure of the Aβ peptide and its interaction with metals (e.g.,
Cu(II)) [28]. Copper, iron, and zinc have been determined in amyloid plaques
from the brains of those with AD [40].
The size of the Aβ peptide varies from 39 to 43 amino acids, produced from
the sequential β- and γ-secretase processing of APP [39]. Cu(II) binds to the
Aβ peptide through tyrosine (Tyr10) and histidine (His13, His14, and His6)
[41]. The Aβ complex of Cu(II) has a high positive reduction potential. The
neurotoxicity of the Aβ peptide has been suggested to relate to the production
of • OH in the copper-mediated oxidation of ascorbate (AScH − ) in the pres-
ence of oxygen and H 2 O 2 (Eqs. 1.1-1.4) [42]:

− •− +

A -Cu II AScH β ( ) + → A -Cu I ASc β ( ) + + H (1.1)

•−

A -Cu II β ( ) + ⋅ + ASc → A -Cu I ASc β ( ) + (1.2)

A -Cu I H O β ( ) + → A -Cu II β ( ) +

•

OH OH +

−

(1.3)

2 2

A -Cu(I) O β + → A -Cu II O β ( ) +

•−

. (1.4)

2 2

1.1.1.2 Parkinson's Disease. PD is a neurodegenerative movement disorder
in which pathophysiological features include the accumulation of intracellular
inclusions and degeneration and death of dopaminergic neurons of substantia
nigra (SN), a part of the midbrain [43]. Mitochondrial dysfunction, oxidative
stress, abnormal protein accumulation, and protein phosphorylation are
important molecular mechanisms that compromise dopamine neuron function