Articulo Hipertension

MOREIRA ET AL. B iol Res 39, 2006, 7-13

Biol Res 39: 7-13, 2006

BR7

Compensatory responses induced by oxidative stress in
Alzheimer disease
PAULA I. MOREIRA1,2, XIONGWEI ZHU1, QUAN LIU1, KAZUHIRO HONDA1,
SANDRA L. SIEDLAK1, PEGGY L. HARRIS1, MARK A. SMITH1 and GEORGE PERRY1
1
2

Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106 USA;Center for Neuroscience and Cell Biology of Coimbra, University of Coimbra, 3004-517 Coimbra, Portugal

ABSTRACT

Oxidative stress occurs early in the progression of Alzheimer disease, significantly before the development of
the pathologic hallmarks, neurofibrillary tangles and senile plaques. In the first stage of development of the
disease, amyloid-β deposition and hyperphosphorylated taufunction as compensatory responses and
downstream adaptations to ensure that neuronal cells do not succumb to oxidative damage. These findings
suggest that Alzheimer disease is associated with a novel balance in oxidant homeostasis.
Key terms: Alzheimer disease, antioxidant therapy, mitochondria, oxidative stress, redox metals

INTRODUCTION

Alzheimer disease (AD) is a common and
complexneurodegenerative disorder that
affects approximately 15 million people
worldwide (Mayeux and Sano, 1999).
Aging is the major risk factor for this
disease that coexists with other causes of
cognitive decline, particularly vascular
dementia. The neuropathological hallmarks
of AD are synapse abnormalities,
intracellular neurofibrillary tangles (NFT)
containing mainly polymerized andhyperphosphorylated tau protein, and the
accumulation of extracellular amyloid
plaques containing mainly amyloid-β (Aβ).
AD is devastating, and despite great strides
in recent years, its causes and mechanisms
are still puzzling. There is accumulating
evidence, however, that oxidative stress
plays an important role in the disease
pathophysiology. While intracellular
oxidative balance is tightlyregulated, the
activation of multiple signaling pathways
and the upregulation of compensatory
mechanisms therefore would be expected to
occur in neurons from AD patients.

Oxidative stress is a prominent event in the
development of Alzheimer disease
Historically, efforts to understand oxidative
status have focused on the concept of
oxidative stress, i.e., the breaching of
oxidantdefenses with consequent cellular
detrimental effects. According to this
definition, the detection of damage resulting
from reactive oxygen or nitrogen species
indicates the existence of oxidative stress.
However, this definition fails to consider the
ability of living systems to dynamically
regulate their defense mechanisms in
response to oxidative stress. Therefore,
increases in oxidativedamage do not
indicate that the cell is succumbing to
oxidative stress given that the cell may have
increased its defenses sufficiently to
compensate for the increased flux of reactive
species responsible for the damage. This
concept is outlined critically by evidence
suggesting that cells failing to compensate
for oxidative imbalance enter into apoptosis,
which in turn leads to death withinhours. It
thus follows that cells can only experience
oxidative stress for short periods of time

Correspondence to: George Perry, Ph.D., Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road,
Cleveland, Ohio 44106 USA, Tel: (1-216) 368-2488, Fax: (1-216) 368-8964, E-mail: george.perry@case.edu
Received: February 7, 2005. Accepted: March 4, 2005.

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M OREIRA ETAL. B iol Res 39, 2006, 7-13

before rapidly dying (Perry et al., 1998a;
Perry et al., 1998b). In chronic degenerative
disorders, such as AD, the cells experiencing
increased oxidative damage must develop
compensatory responses aimed to avoid or,
at least, reduce cellular damage or death.
It has been shown that increased oxidative
damage is a prominent and early feature of
vulnerable...