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Molecular Neurobiology

, Volume 41, Issue 2–3, pp 159–171 | Cite as

Mitochondrial Dysfunction: Common Final Pathway in Brain Aging and Alzheimer’s Disease—Therapeutic Aspects

  • Walter E. MüllerEmail author
  • Anne Eckert
  • Christopher Kurz
  • Gunter Peter Eckert
  • Kristina Leuner
Article

Abstract

As a fully differentiated organ, our brain is very sensitive to cumulative oxidative damage of proteins, lipids, and DNA occurring during normal aging because of its high energy metabolism and the relative low activity of antioxidative defense mechanisms. As a major consequence, perturbations of energy metabolism including mitochondrial dysfunction, alterations of signaling mechanisms and of gene expression culminate in functional deficits. With the increasing average life span of humans, age-related cognitive disorders such as Alzheimer’s disease (AD) are a major health concern in our society. Age-related mitochondrial dysfunction underlies most neurodegenerative diseases, where it is potentiated by disease-specific factors. AD is characterized by two major histopathological hallmarks, initially intracellular and with the progression of the disease extracellular accumulation of oligomeric and fibrillar β-amyloid peptides and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. In this review, we focus on findings in AD animal and cell models indicating that these histopathological alterations induce functional deficits of the respiratory chain complexes and therefore consecutively result in mitochondrial dysfunction and oxidative stress. These parameters lead synergistically with the alterations of the brain aging process to typical signs of neurodegeneration in the later state of the disease, including synaptic dysfunction, loss of synapses and neurites, and finally neuronal loss. We suggest that mitochondrial protection and subsequent reduction of oxidative stress are important targets for prevention and long-term treatment of early stages of AD.

Keywords

Mitochondrial dysfunction Alzheimer’s disease Aging Oxidative stress Ginkgo biloba extract Piracetam Dimebon 

Abbreviations

Amyloid beta

AD

Alzheimer’s disease

APP

Amyloid precursor protein

COX

Cytochrome c oxidase

dG

8-oxo-2′-Deoxyguanosine oxo8

FAD

Familial Alzheimer’s disease

GPx

Glutathione peroxidase

HNE

4-Hydroxynonenal

MDA

Malondialdehyde

Mn-SOD

Manganese superoxide dismutase

mtDNA

Mitochondrial DNA

PS

Presenilin

RNS

Reactive nitrogen species

ROS

Reactive oxygen species

SOD

Superoxide dismutase

SNP

Sodium nitroprusside

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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Walter E. Müller
    • 1
    Email author
  • Anne Eckert
    • 3
  • Christopher Kurz
    • 2
  • Gunter Peter Eckert
    • 2
  • Kristina Leuner
    • 2
  1. 1.Department of Pharmacology, BiocenterUniversity of FrankfurtFrankfurtGermany
  2. 2.Department of Pharmacology, BiocenterUniversity of FrankfurtFrankfurtGermany
  3. 3.Neurobiology Research LaboratoryPsychiatric University ClinicBaselSwitzerland

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