Alzheimer's disease as a calciumopathy

• Autorzy: Wojda U.
• Języki publikacji: EN

Abstrakty

EN

Alzheimer’s disease (AD) is the most common age-related neurodegenerative dementia attributed to the amyloid beta (Aβ) deposition in the brain. Analysis of rare familiar (FAD) cases with mutations in presenilin, the proteins responsible for generation of Aβ from its precursor APP, firmed the ‘amyloid hypothesis’ of AD etiology. However, anti-amyloid therapies failed indicating that AD pathogenesis is more complex and involves additional mechanisms. Affected brain areas of AD patients and of animal FAD models showed increased levels of intracellular Ca2+, alterations in expression levels of Ca2+- signaling proteins and increased activation of Ca2+-dependent enzymes. Based on these data, the ‘Ca2+ hypothesis of AD’ has been proposed. Ca2+ contributes to the development of AD by Ca2+-triggered ER and mitochondrial dysfunction, and Ca2+- dependent changes in gene expression. The elevated cytosolic Ca2+ levels affect synaptic stability and function, and can activate death signaling. Moreover, the augmented cellular Ca2+ levels affect Aβ generation. In turn, Aβ generation potentiate Ca2+ dyshomeostasis in several ways. For example, Aβ causes impairment of NMDARs signaling while the released APP intracellular domain modulates Ca2+ homeostasis as the regulator of IP3-mediated Ca2+ efflux from the ER. Mutant presenilins contribute to Ca2+ dyshomeostasis as impaired ER Ca2+ leak channels and via interactions with Ca2+-signaling proteins such as calsenilin. Taken together, a growing body of evidence indicates that AD pathogenesis is based on the interplay between Ca2+ dyshomeostasis and neuropathological hallmarks of AD such as Aβ and mutated PS1. Thus, stabilizers of neuronal Ca2+ homeostasis and signaling may have therapeutic potential for AD treatment.

• Wydawca: -
• Czasopismo: Acta Neurobiologiae Experimentalis
• Rocznik: 2011
• Tom: 71
• Numer: S
• Opis fizyczny: p.27

Twórcy

autor

Wojda U.

• Laboratory of Neurodegeneration, International Institute of Molecular and Cell Biology, Warsaw, Poland

Uwagi

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