Vascular Oxidative Stress and Mitochondrial Failure in the Pathobiology of Alzheimer’s Disease: A New Approach to Therapy

Author(s): Marta Sochocka, Euphrosyni S. Koutsouraki, Kazimierz Gasiorowski, Jerzy Leszek.

Journal Name: CNS & Neurological Disorders - Drug Targets

Volume 12 , Issue 6 , 2013

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Abstract:

Vascular and metabolic dysfunctions and mitochondrial failure are now believed to be contributors to Alzheimer’s disease (AD) pathogenesis. Vascular dysfunction includes reduced cerebral blood flow (CBF), blood-brain barrier (BBB) disturbances and cerebral amyloid angiopathy (CAA). Mitochondrial failure results in deregulation of Ca2+ homeostasis and elevated reactive oxygen species (ROS) generation, both of which are linked to neurotoxicity. Increased levels of ROS stimulate proinflammatory gene transcription and release of cytokines, such as IL-1, IL-6, and TNF-α, and chemokines, thereby inducing neuroinflammation. Conversely, inflammatory reactions activate microglia and astrocytes to generate large amounts of ROS, so neuroinflammation could be perceived as a cause and a consequence of chronic oxidative stress. The interaction between oxidative stress and neuroinflammation leads to amyloid-β (Aβ) generation. The deposition of Aβ peptide in the brain generates a cascade of pathological events, including the formation of neurofibrillary tangles (NFTs), inflammatory reactions, increased oxidative stress and mitochondrial dysfunction, which are causative factors of cell death and dementia. The purpose of this paper is to provide current evidence on vascular dysfunction and mitochondrial failure, both in neurons and glia and in brain vascular wall cells in the context of potential application for treatment of AD and other neurodegenerations.

Keywords: Alzheimer's disease, mitochondrial failure, neurodegeneration, neuroinflammation, ROS, vascular dysfunction.

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Article Details

VOLUME: 12
ISSUE: 6
Year: 2013
Page: [870 - 881]
Pages: 12
DOI: 10.2174/18715273113129990072
Price: $58

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