Calcium dyshomeostasis and neurotoxicity of Alzheimer’s β-amyloid protein

Abstract

Neurotoxicity of Alzheimer’s β-amyloid protein (AβP) is central to the pathogenesis of Alzheimer’s disease (AD). Recent approaches have emphasized the importance of AβP oligomerization, which causes synaptic degeneration and neuronal loss, finally leading to the pathogenesis of AD. Although the precise molecular mechanism of AβP neurotoxicity remains elusive, our and other numerous findings have demonstrated that AβP directly incorporated into neuronal membranes formed calcium-permeable ion channels (amyloid channels) and resulted in an abnormal elevation of the intracellular calcium levels. The formation of amyloid channels and the abnormal increase of intracellular Ca²⁺ have also been commonly observed in other neurodegenerative diseases, including conformational diseases such as prion disease or dementia with Lewy bodies. This article reviews the current understanding of the pathology of AD based on the hypothesis that the disruption of calcium homeostasis through amyloid channels may be the molecular basis of AβP neurotoxicity. The potential development of preventive agents is also discussed.

Keywords::

• apoptosis
• membrane fluidity
• neurosteroid
• oligomerization
• synapse
• zinc

Financial & competing interests disclosure

This work was partially supported by a Grant-in Aid for Scientific Research for the Ministry of Education, Culture, Sports, Science and Technology of Japan and by a Grant from Cooperation for Innovative Technology and Advanced Research in Evolutional Area (CITY AREA) by Miyazaki Prefectural Industrial Support Foundation. I thank Editage, Cactus Communications Pvt. Ltd. for correcting English and for writing assistance. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing assistance from Editage, Cactus Communications Pvt. Ltd was utilized in the production of this manuscript.