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Molecular Neurobiology

, Volume 46, Issue 1, pp 186–193 | Cite as

From Mitochondrial Dysfunction to Amyloid Beta Formation: Novel Insights into the Pathogenesis of Alzheimer’s Disease

  • Kristina LeunerEmail author
  • Walter E. Müller
  • Andreas S. Reichert
Article

Abstract

The non-Mendelian sporadic Alzheimer’s disease (AD) is the most frequent form of dementia diagnosed worldwide. The most important risk factor to develop sporadic AD is aging itself. Next to hyperphosphorylated Tau, intracellular amyloid beta (Aß) oligomers are known to initiate a cascade of pathological events ranging from mitochondrial dysfunction, synaptic dysfunction, oxidative stress, and loss of calcium regulation, to inflammation. All these events are considered to play an important role in the progressive loss of neurons. The molecular mechanisms determining the balance between Aß production and clearance during the progression of the disease are not well understood. Furthermore, there is cumulating evidence that Aß formation impairs mitochondrial function and that mitochondrial dysfunction is an early event in the pathogenesis of AD. On the other hand, mitochondrial dysfunction, in particular increased formation of mitochondrially derived reactive oxygen species, promote Aß formation. Here, we review these latest findings linking mitochondrial dysfunction and Aß formation. We propose that mitochondrial dysfunction, which is well-known to increase with age, is an initial trigger for Aß production. As Aß itself further accelerates mitochondrial dysfunction and oxidative stress, its formation is self-stimulated. Taken together, a vicious cycle is initiated that originates from mitochondrial dysfunction, implying that AD can be viewed as an age-associated mitochondrial disorder. The proposed mechanism sheds new light on the pathophysiological changes taking place during the progression of AD as well as in the aging process.

Keywords

Alzheimer’s disease Amyloid beta formation Aging Mitochondrial dysfunction 

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Kristina Leuner
    • 1
    Email author
  • Walter E. Müller
    • 2
  • Andreas S. Reichert
    • 3
  1. 1.Molecular and Clinical PharmacyFAU Erlangen/NürnbergErlangenGermany
  2. 2.Department of Pharmacology, Biocenter NiederurselGoethe University Frankfurt am MainFrankfurt am MainGermany
  3. 3.Mitochondrial Biology, Buchmann Institute for Molecular Life SciencesGoethe University Frankfurt am Main, Fachbereich MedizinFrankfurt am MainGermany

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