Neuronal death and survival under oxidative stress in Alzheimer and Parkinson diseases.
Neuronal death is a common feature in neurodegenerative diseases including Alzheimer disease (AD) and Parkinson disease (PD). This occurs over years, not the minutes of classically defined apoptosis, and neurons show both responses of apoptosis and regeneration, evidenced by accumulated oxidative insult and attempts at cell cycle re-entry. There is recent evidence suggesting that several known gene mutations in causing familial AD (amyloid beta protein precursor, presenilin-1, or presenilin-2 gene) and familial PD (Parkin, PINK-1, or DJ-1 gene) are associated with increased oxidative stress. Also, several known genetic (e.g. Apolipoprotein Eepsilon4 variant) and environmental (e.g. metals or pesticides exposure) risk factors of sporadic AD and/or PD are associated with increased oxidative stress. In concord, patients at the preclinical stages of AD and PD as well as cellular and animal models of the diseases provide consistent evidence that oxidative insult is a significant early event in the pathological cascade of AD and PD. In contrast to the general aspects of the pathological hallmarks, aggregation of the disease-specific proteins such as amyloid-beta, tau, and alpha-synuclein may act as a compensatory (survival) response against the oxidative insult via the mechanism that the disease-specific structures sequester redox-active metals. Expanding knowledge of the molecular mechanisms of organism longevity indicates that pro-longevity gene products such as forkhead transcription factors and sirtuins are involved in the insulin-like signaling pathway and oxidative stress resistance against aging. An enhancement of the pro-longevity signaling (e.g. caloric restriction) may be a promising approach as anti-oxidative strategy against age-associated neurodegenerative diseases.
Nunomura
A
A
Department of Psychiatry and Neurology, Asahikawa Medical College, Asahikawa 078-8510, Japan. nuno@asahikawa-med.ac.jp
Moreira
P I
PI
Lee
H G
HG
Zhu
X
X
Castellani
R J
RJ
Smith
M A
MA
Perry
G
G
D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D016923:Cell Death / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D006801:Humans; D009474:Neurons / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D010300:Parkinson Disease / Q000473:pathology / Q000503:physiopathology*