Oxidative Stress and AD: Mechanisms and Therapeutics 615
These findings establish a link between oxidative stress and mitochondria, cre-
ating a pathological feedback loop, although in other cell types such as astrocytes,
which are known to regulate glutathione availability, mitochondria are unaffected
(Pope et al., 2008).
Mitochondria are also susceptible to apoptotic pathways, mediated through mem-
bers of (a) Bcl-2 family (Bid, Bad, and Bax), (b) death receptor pathway, and
(c) endoplasmic-reticulum-specific pathway. The final result of these three pathways
is the activation of caspases (Ferri and Kroemer, 2001). It has been reported that the
neurons exhibiting increased oxidative damage in AD are coincident with striking
and significant increase in cytochrome oxidases and mtDNA (Hirai et al., 2001).
Cytochrome oxidase is found in the neuronal cytoplasm and mtDNA in vacuoles
associated with lipofuscin. Furthermore, lipoic acid antisera specifically mark lipo-
fuscin in AD, suggesting increased autophagocytosis (Moreira et al., 2007). Also, a
significant reduction of intact mitochondria, as well as a reduction in microtubules,
is found in AD (Cash et al., 2003). Oxidative stress markers, mtDNA deletion,
and abnormalities in mitochondrial structure in the vascular walls of AD cases
are also increased (Aliev et al., 2004). In addition to changes in mitochondrial
enzymes, mitochondrial structure, localization, and mobility are all changed in AD.
Specifically, markers for mitochondrial fission and fusion are altered in models of
AD and are affected by Aβ oligomers, which impair mitochondrial function, leading
to energy hypometabolism and elevated reactive oxygen species production (Wang
et al., 2007b, 2008a,b).
In sum, it is apparent that mitochondria and oxidative stress are closely related
and together, through different pathways, contribute to the neurodegenerative
process.
3.3 Metals
The other important source of free radicals comes from redox-active metals.
Strikingly, NFT and Aβ plaques were found coincident with overaccumulation of
iron in the hippocampus, cerebral cortex, and basal nucleus of Meynert (Lovell et al.,
1998). Iron is an important cause of oxidative stress in AD through the Fenton reac-

tion. Aβ is also a substrate for hydroxyl radicals and, in the presence of iron, it has
been reported that cleavage and synthesis of Aβ are promoted (Atwood et al., 1999;
Rogers et al., 2002).
Copper can also participate in the Fenton reaction to generate ROS (Huang et al.,
1999b; Finefrock et al., 2003) and is affected by Aβ (Hayashi et al., 2007; Nakamura
et al., 2007). Furthermore, iron and copper in their redox competent states are bound
to NFT and Aβ deposits (Smith et al., 1997a; Sayre et al., 2000). Nevertheless, the
exact role of copper and iron in their redox competent states remains to be eluci-
dated. In this regard, it is been suggested that mitochondrial dysfunction, acting in
concert with cytoskeletal pathology, serves to increase redox-active heavy metals
and initiates a cascade of abnormal events culminating in AD pathology (Castellani
et al., 2004).
616 S. Mondragón-Rodríguez et al.
4 Current and Future Pharmacological Treatments
for Alzheimer Disease
An enormous effort has been devoted to developing treatments for the clinical
symptoms of AD. Cholinesterase inhibitors, antiglutamatergic treatment, β- and
γ-secretase inhibitors, cholesterol-lowering drugs, Aβ immunotherapy, nonsteroidal
anti-inflammatory drugs, Aβ channel blockers, hormonal replacement therapy, and
antioxidant therapies are the current pharmacological options for treatment of AD
(Bartus et al., 1982; Schenk et al., 1999; Pratico and Trojanowski, 2000; Dovey
et al., 2001; Golde and Eckman, 2001; Nunomura et al., 2001; Cholerton et al.,
2002; Farlow et al., 2003; Perry et al., 2003; Moreira et al., 2006; Diaz et al., 2009;
Lopez-Bastida et al., 2009; Moriguchi et al., 2009).
Cholinergic transmission plays a fundamental role in cognitive function. Due
to a reported decrease of cholinergic function in the neocortex and hippocam-
pus, several acetylcholinesterase inhibitors have been used to treat AD in the past
few years, such as tacrine, donepezil, rivastigmine, and galactine (Lleo et al.,
2005; Moriguchi et al., 2009). Acetylcholinesterase inhibitors can delay cogni-
tive impairment for at least six months (Takeda et al., 2006). Indeed, these drugs

have been found to possess some antioxidant properties as well as neuroprotec-
tive properties (Fernandez-Bachiller et al., 2009). However, they were recently
shown to have opposing effects on blood pressure and cerebral perfusion (Claassen
et al., 2009).
The most important excitatory neurotransmitter in the central nervous system
(CNS) is glutamate, reported to regulate Ca
2+
accumulation through excessive acti-
vation of NMDA receptors. Memantine is an NMDA antagonist that has been used
to treat neurological syndromes and cognitive dysfunction (Farlow et al., 2003). A
small beneficial effect of memantine was observed at six months of treatment in
moderate to severe AD (Areosa et al., 2005).
Numerous studies have supported the idea that an oxidative event is critical in
AD. It is thought that Aβ is capable of generating reactive oxygen species. However,
the source of Aβ toxicity has yet to be established (Rottkamp et al., 2001). Although
deposition of Aβ into senile plaques is by no means specific to AD, several treat-
ments against Aβ deposition are currently in use. In this context β- and γ-secretase
inhibitors have been used therapeutically. Although the main goal is to block the
production of Aβ (Josien, 2002), γ-secretase inhibitors also block the proteolytic
processing and function of Notch, which i s essential for brain morphogenesis (Louvi
et al., 2004). In contrast, no side effects have been found with β-secretase inhibitors
in knock-out mice (Dominguez et al., 2005). Indeed, novel therapeutic strategies
contemplate the use of dual effectors, such as the new dual inhibitor of acetyl-
cholinesterase and β-secretase (Zhu et al., 2009). The preliminary data in transgenic
mice looks promising.
Cholesterol has been reported to negatively regulate α-secretase, whereas β- and
γ-secretase activities are positively regulated by cholesterol (Golde and Eckman,
2001). Disappointingly, a three-year trial with pravastatin (a cholesterol-lowering
Oxidative Stress and AD: Mechanisms and Therapeutics 617
drug) showed no significant effect on cognitive function in elderly individuals

(Shepherd et al., 2002).
Aβ immunization is a novel approach to AD treatment. Simple immunization
with Aβ42 in transgenic mice blocked deposition of amyloid and cleared existing
amyloid (Schenk et al., 1999; Boche et al., 2008). Recently, increased dendritic
spine formation in PDAPP transgenic mice was found after amyloid clearance, sug-
gesting functional recovery of neural circuits (Spires-Jones et al., 2009). However,
active vaccination with Aβ in patients with mild to moderate AD in a Phase II trial
showed a CNS inflammatory response (Monsonego et al., 2003). The meningoen-
cephalitis that occurred in some of the patients was reported to be unrelated to the
anti-Aβ antibody titer (Hock et al., 2003; Wilcock and Colton, 2008), but rather
to the involvement of a specific T-cell inflammatory response (Ferrer et al., 2004).
Others have speculated that the adverse effects were due to external contamination
during lumbar punctures, which were required as part of the protocol (Dodel et al.,
2003). Furthermore, Fox and colleagues (Fox et al., 2005) showed, by standard vol-
umetry, that the brains of vaccinated individuals lost tissue and gained ventricular
volume faster than did brains of individuals vaccinated with placebo. If, as we sus-
pect, Aβ is functioning as an antioxidant, removal of Aβ by immunization and/or
other methods may actually exacerbate disease progression.
Extensive epidemiological data suggest a gender-based predisposition that is spe-
cific to AD such that there is a higher prevalence (Jorm et al., 1987; Breitner et al.,
1988; Rocca et al., 1991; McGonigal et al., 1993) and incidence (Jorm and Jolley,
1998) of AD in women. Hormone replacement therapy protection against AD is
restricted to administration during a “critical period” that constitutes the climacteric
years. Efficacy is variable when administered after such time (Rapp et al., 2003)
or during the latent preclinical stage of AD, which usually occurs much later in
life (Resnick and Henderson, 2002; Craig and Murphy, 2009; Henderson, 2009;
Hogervorst et al., 2009). The mechanism(s) relating hormones and pathology is
(are) being actively pursued; it has been proposed that luteinizing hormone may
contribute to AD pathology through an amyloid-dependent mechanism (Casadesus
et al., 2006; Webber et al., 2007; Berry et al., 2008), that again underlies the bias

towards females developing AD. In this regard, previous reports demonstrate a
twofold increase in the gonadotropin LH in AD patients compared to age-matched
control subjects (Bowen et al., 2000; Short et al., 2001; Webber et al., 2007). Thus,
the presence of functional LH receptors was, at least i n part, responsible for the cog-
nitive decline seen in transgenic mice (Casadesus et al., 2007). Additionally, it has
been reported that increased serum LH, rather than lower serum-free testosterone, is
associated with the accumulation of Aβ in plasma (Verdile et al.,
2008). Therefore,
therapeutic strategies that are targeted towards decreasing LH may prove successful
in treatment of AD (Webber et al., 2006, 2007; Casadesus et al., 2008).
Because chronic inflammation is associated with AD, several anti-inflamatory
drugs have been tested including celecoxib (sc-125; sc-560), r-flurbiprofen,
naproxen, and rocoxib (Szekely et al., 2004). Unfortunately, no consistent improve-
ment in AD symptoms after treatment has been reported.
618 S. Mondragón-Rodríguez et al.
The involvement of oxidative stress in AD has opened a new door for potential
therapeutic targets. In this regard, several antioxidants are currently in clinical tri-
als such as Idebenone, α-Lipoic acid, acetyl-L-carnitine (ALC), vitamin E, vitamin
C, flavonoids, β-carotene, gingko biloba, and metal-chelating agents. Idebenone is
a metabolic antioxidant and is normally synthesized as part of the mitochondrial
oxidative phosphorylation system. Improvements in clinical status after treatment
with idebenone have been shown in a dose-dependent manner compared to placebo
and tacrine (Thal et al., 2003).
α-Lipoic acid is another metabolic antioxidant that can recycle other antioxi-
dants such as glutathione. Patients treated with α-Lipoic acid exhibited stabilization
of cognitive measures (Hager et al., 2001). Acetyl-L-carnitine (ALC) is another
metabolic antioxidant that acts as an intracellular carrier of acetyl groups across the
inner mitochondrial membrane. Treatment with ALC showed a 38% response rate,
and 50% when combined with acetyl cholinesterase inhibitors (Montgomery et al.,
2003).

Vitamins, flavonoids, and terpenoids are examples of direct antioxidants
(McShea et al., 2008; Ramiro-Puig et al., 2009). Vitamin E and selegiline appear to
delay the time of progression to severe dementia in AD patients (Sano et al., 1997;
Grundman, 2000). Vitamin E is the most important lipid-soluble chain-breaking
natural antioxidant in mammalian cells and is able to cross the blood–brain barrier
and accumulate at therapeutic levels in the brain, where it reduces lipid peroxidation
(Veinbergs et al., 2000). In a cross-sectional study of 4809 elderly, decreasing serum
levels of vitamin E per unit of cholesterol were consistently associated with decreas-
ing cognitive function, whereas serum levels of vitamins A and C, β-carotene, and
selenium were not associated with poor memory performance (Perkins et al., 1999).
The Chicago Health and Aging Project with samples of 2889 community residents
aged 65–102 years found that supplementary or dietary intake of vitamin E, but
not vitamin C or carotenes, was inversely related to cognitive decline (Morris et al.,
2002b). However, data from prospective studies relating intake of vitamin E and risk
of AD are conflicting. The Chicago Health and Aging Project found that dietary, but
not supplementary, intake of vitamin E was associated with a lowered risk of AD
only among noncarriers of the ApoE ε4 allele (Morris et al., 2002a). Furthermore,
in the Washington Heights–Inwood Columbia Aging Project, no association was
found between dietary or supplementary intake of vitamin E and a decreased risk
of AD (Luchsinger et al., 2003). The lack of efficacy of vitamin E in preventing the
progression from MCI to AD indicates that single supplementary vitamin treatment
has no significant affect in the secondary prevention of AD, which is consistent
with the previous cohort studies on the progression to AD from the cognitively nor-
mal elderly. Gingko biloba contains, among other things, flavonoids and terpenoids.
No differences in soluble Aβ and hippocampal Aβ were found in mice treated with
Gingko biloba, although they showed improved spatial memory retention (Stackman
et al., 2003).
Thus, re-examination of metal-chelating agents, classical indirect antioxidants,
is warranted. NFT and senile plaques have been shown to contain redox-active tran-
sition metals (Smith et al., 1997a; Sayre et al., 2000) and may exert pro-oxidant

Oxidative Stress and AD: Mechanisms and Therapeutics 619
or maybe antioxidant activities, depending on the local microenviroment. Aβ trans-
genic mice exhibited a 40% decrease in Aβ deposition after a nine-week treatment
with clioquinol, a metal–protein chelating agent (Cherny et al., 2001). In two
familial AD patients, increases in cerebral glucose metabolism were present after
extended clioquinol treatment (Ibach et al., 2005).
5 Conclusion
As discussed in this chapter, oxidative stress plays an important role in AD, but
more importantly, oxidative stress seems to be an early event, preceding classic
fibril formation (Aβ plaques and NFT). Fibril formation can be explained as a com-
pensatory mechanism that eventually enhances oxidative stress by increasing ROS
levels among many other free radicals. In this scenario, deposition of Aβ in the
extracellular environment and tau protein in the intracellular environment can be
explained as an imbalance and tragic consequence. If this hypothesis is current, the
current pharmacological treatments will not provide a solution, because the majority
are directed against the fibril structures. In contrast, antioxidant strategies may be
helpful in treating AD symptoms, although significant extended benefits have not
been realized to date.
In sum, the damage observed in the brain tissue of AD patients that is enhanced
by the fibril structures may be minimized with a healthy daily diet, exercise, and
intellectual activities as the best option so far.
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