Molecular Aspects of Neurodegeneration and Neuroprotection

Association of Mitochondrial Signaling in Alzheimer’s Disease and Hypoxia

Author(s): Cristina Carvalho, Sonia C. Correia, Renato X. Santos, Susana Cardoso, Paula I. Moreira, Xiongwei Zhu, Mark A. Smith and George Perry

Pp: 50-61 (12)

Doi: 10.2174/978160805092511101010050

* (Excluding Mailing and Handling)

Abstract

Neurodegenerative diseases, particularly those associated with aging such as Alzheimer’s disease, represent a significant public health concern. The development of effective treatments is, however, hindered by the complex, multigenic nature of these diseases and by their poorly understood molecular pathophysiology. Mitochondria seem to play a primary role in neurodegeneration, due to the high energy demand of the brain. These organelles are the main producers of energy through the tricarboxylic acid cycle and host a high number of biochemical pathways including those involved in storage and maintenance of intracellular calcium levels, cellular homeostasis and survival pathways. However, mitochondria are a double edge sword. In the presence of certain oxidative stimuli, for instance, when oxygen demand exceeds supply (hypoxia), mitochondria can activate several death pathways. Indeed, hypoxia has been implicated in several neurodegenerative diseases including Alzheimer’s disease. Current knowledge supports the idea that during hypoxic events mitochondrial complex III produces high levels of reactive oxygen species (ROS), which play a key role in the regulation of the transcription factor hypoxia inducible factor 1 that triggers several death effectors. In this chapter we will discuss the involvement of mitochondria in AD putting focus on the mitochondrial pathways activated by hypoxia, which could eventually lead neurodegenerative events.


Keywords: Alzheimer’s disease; mitochondrial dysfunction; reactive oxygen species; cerebral amyloid angiopathy; β- secretase; Aβ neurotoxicity

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