Kainic Acid Impairs the Memory Behavior of APP23 Mice by Increasing Brain Amyloid Load through a Tumor Necrosis Factor-α-Dependent Mechanism

Journal of Alzheimer's Disease : JAD
Yang RuanXiang-Yu Zheng

Abstract

Kainic acid (KA) was recently identified as an epileptogenic and neuroexcitotoxic agent that is responsible for inducing learning and memory deficits in various neurodegenerative diseases, such as Alzheimer's disease (AD). However, the mechanism by which KA acts upon AD remains unclear. To this end, we presently investigated the roles of KA in processing amyloid-β protein precursor (AβPP) and amyloid-β protein (Aβ) loads during the course of AD development and progression. Specifically, KA treatment clearly caused the upregulation of tumor necrosis factor α (TNF-α) via activation of the PI3-K/AKT, ERK1/2, and p65 pathways in glial cells. TNF-α secreted from glial cells was then found to be responsible for stimulating the expression of BACE-1 and PS1/2, which resulted in the production and deposition of Aβ in neurons. Finally, the accumulation and aggregation of Aβ lead to the cognitive decline of APP23 mice. These results indicate that KA accelerates the progression of AD by inducing the crosstalk between glial cells and neurons.

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