Vascular oxidative stress in Alzheimer disease.
Alzheimer disease and cerebrovascular dementia are two common causes of dementia and, by present diagnostic criteria, are mutually exclusive using vascular pathology as an arbitrary demarcation in differential diagnosis. However, evidence from epidemiological, neuropathological, clinical, pharmacological, and functional studies suggest considerable overlap in risk factors and pathological changes suggesting shared common pathogenic mechanisms between these two diseases such that vascular factors play a vital role in the pathogenesis of Alzheimer disease. A high energy demand and lack of an endogenous fuel reserve make the brain highly dependent upon a continuous blood supply where disruption of cerebral blood vessels and blood flow can have serious consequences on neural activities. Indeed, many studies implicate metabolic defects in Alzheimer disease, such a reduced brain metabolism is one of the best documented abnormalities in the disease. Notably, since endothelial reactive oxygen species such as nitric oxide act as vasodilators at low concentrations, increased production coupled with elevated reactive oxygen species scavenging of nitric oxide, can lead to reduced bioavailability of nitric oxide and increased oxidative stress that damage sensitive vascular cells. In this respect, we and others have demonstrated that oxidative stress is one of the earliest pathological changes in the brain of Alzheimer disease patients and plays a critical role in the vascular abnormalities underlying metabolic defects in Alzheimer disease. Here, we discuss vascular factors in relation to Alzheimer disease and review hypoperfusion as a potential cause by triggering mitochondrial dysfunction and increased oxidative stress initiating the pathogenic process.
Zhu
Xiongwei
X
Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Smith
Mark A
MA
Honda
Kazuhiro
K
Aliev
Gjumrakch
G
Moreira
Paula I
PI
Nunomura
Akihiko
A
Casadesus
Gemma
G
Harris
Peggy L R
PL
Siedlak
Sandra L
SL
Perry
George
G
D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D001921:Brain / Q000098:blood supply / Q000378:metabolism* / Q000503:physiopathology; D002536:Cerebral Arteries / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000502:physiology; D015140:Dementia, Vascular / Q000378:metabolism* / Q000503:physiopathology; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*
D009569:Nitric Oxide