Ahram Jang, Hyunjeong Liew, Yun-Mi Kim, Heesoon Choi, Saeromi Kim, Sang Hyung Lee, Toshio Ohshima, Katsuhiko Mikoshiba and Yoo-Hun Suh Pages 829 - 843 ( 15 )
The activities of CDK5 and p35 are thought to be important in the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD). We studied the effect of p35 deletion in Tg2576 mice, which is an AD animal model. To obtain the desired mice, we crossed p35<sup>-/-</sup> with Tg2576 mice. The resulting p35<sup>-/-</sup>/Tg2576 (KO/Tg) mice displayed higher mortality rates and exhibited impaired spatial learning and memory at 6 months of age. Using immunohistochemical and biochemical approaches, we observed a reduction in the expression of pre- and post-synaptic markers such as NMDAR1, synaptophysin and GluR1. In addition, the intensity of MAP-2-positive dendrites extending from neuronal cell bodies was significantly decreased in KO/Tg mice compared with KO/WT and WT/Tg mice. We also detected increased neuronal cell death in the hippocampus, along with thinned and collapsed morphological changes in the alveus region and a dramatic increase in the number of microglial cells. Microglial infiltration in the hippocampus could result in the increased secretion of the soluble high mobility group box-1 protein (HMGB-1). The secretion of HMGB-1 is increased by Aβ, and secretion of HMGB-1 promotes neuronal cell death. Moreover, we found that HMGB-1 secretion induced by Aβ in KO/Tg mice gave rise to ER-mediated cell death. In summary, during the stages of KO/Tg mice model, the microglial infiltration and secretion of soluble HMGB-1 were significantly increased in the hippocampus. These conditions promote neuronal death, synaptic destruction and behavioral deficits.
p35, microglial infiltration, HMGB-1, memory impairment, Alzheimer’s disease, synaptic dysfunction.
, , , , , , , , Department of Pharmacology, College of Medicine, Seoul National University, 28 Yongon-dong, Chongno-Gu, Seoul and Department of Convergence Brain Research, Korea Brain Research Institute (KBRI), Daegu, Korea.