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

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 Ca(2+) 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.

Neuroprotective effect of acute melatonin treatment on hippocampal neurons against irradiation by inhibition of caspase-3

“…In addition to activating cell death, previous studies have demonstrated that caspase-3 also has fundamental roles in signal transduction (10,11 of the normal cellular metabolism of oxygen; however, a dramatic increase in ROS levels may lead to oxidative stress. It has been demonstrated that ROS induced by ionizing radiation are capable of triggering oxidative cellular damage and stimulating the activation of intracellular signaling pathways (12). The brain, which is a major metabolizer of oxygen with relatively poor protective antioxidant mechanisms, is particularly vulnerable to the ROS.…”

Resveratrol relieves ischemia‑induced oxidative stress in the hippocampus by activating SIRT1

“…ROS produced at the early phase of neuronal apoptosis act as mediators of intracellular apoptotic signaling cascades (5), and pathologically accelerate the release of cytochrome c from mitochondria (6,7). ROS production evidently increases following ischemia, which leads to oxidative stress (8)(9)(10). Studies have revealed that at least some of the effects on cells of exposure to ROS are similar to those of ischemic insult.…”

Combinatorial Vaccine against Complement Factor C5a and Amyloid Beta: A New Therapeutic Approach in Alzheimers Disease

“…Consequently, microglia become activated either by a direct interaction with misfolded Aβ molecules via pattern recognition receptors (PRR), or by complement activation in the response to Aβ depositions which leads to the formation of the pro-inflammatory molecule C5a [14]. Enhanced microglia activation then leads to excessive release of proinflammatory cytokines [20], chemokines [21,22], and further complement components [23,24], as well as the release of reactive oxygen and nitrogen species [25,26]. These pro-inflammatory mediators cause a number of stress conditions which, in turn, are supposed to reinforce Aβ production and aggregation [28,30,31,42,43].…”

“…Aβ aggregates cause direct cytotoxicity and self-propagation, but also a constant, selfsustaining inflammatory environment by prolonged activation of astroglial [17,18] and microglial cells [19]. Activation of microglia by Aβ and complement is supposed to promote the excessive release of proinflammatory cytokines [20], chemokines [21,22], and further complement components [23,24], as well as the release of reactive oxygen and nitrogen species [25,26], altogether leading to dysfunction and loss of synapse signaling [27]. Pro-inflammatory mediators provoke a number of stress conditions which, in turn, can enhance APP production and processing to amyloid peptides (Aβ 1-42) [28][29][30][31].…”