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-/- with Tg2576 mice. The resulting p35-/-/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.