Abstract
Increasing evidence suggests that the metal homeostasis is involved in the pathogenesis of various neurodegenerative diseases including senile type of dementia such as Alzheimer’s disease, dementia with Lewy bodies, and vascular dementia. In particular, synaptic Zn2+ is known to play critical roles in the pathogenesis of vascular dementia. In this article, we review the molecular pathways of Zn2+-induced neurotoxicity based on our and numerous other findings, and demonstrated the implications of the energy production pathway, the disruption of calcium homeostasis, the production of reactive oxygen species (ROS), the endoplasmic reticulum (ER)-stress pathway, and the stress-activated protein kinases/c-Jun amino-terminal kinases (SAPK/JNK) pathway. Furthermore, we have searched for substances that protect neurons from Zn2+-induced neurotoxicity among various agricultural products and determined carnosine (β-alanyl histidine) as a possible therapeutic agent for vascular dementia.
Highlights
Senile dementia is a serious problem for our rapidly aging society
Based on our recent findings about the involvements of the production of reactive oxygen species (ROS) and the stress-activated protein kinases/c-Jun amino-terminal kinases (SAPK/JNK) pathway [10], we developed a hypothetical scheme about these molecular pathways of Zn2+-induced neurotoxicity
We have developed a system for quantitative analysis of carnosine using high-performance liquid chromatography (HPLC) [20] and demonstrated here the developmental changes of the amount of carnosine and its analogues in the brain
Summary
Senile dementia is a serious problem for our rapidly aging society. It is characterized by profound memory loss and inability to form new memories in older adults, and its prevalence increases with age. Senile dementia is mainly divided into Alzheimer’s disease (AD), vascular dementia (VD), and dementia with Lewy bodies (DLB). Both AD and DLB are characterized by the deposition of abnormally accumulated proteins; β-amyloid protein (AβP) in AD and α-synuclein in DLB [1,2]. Substances that attenuate Zn2+-induced neurotoxicity may become potential drugs for the treatment or prevention of VD [11]. Based on this idea, we have developed a convenient screening system for such substances, and examined extracts of various agricultural products, e.g., fruits, vegetables, and fish. We discussed the perspectives of carnosine supplement therapy for the prevention of VD
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