Chronic stress-mutated presenilin 1 gene interaction perturbs neurogenesis and accelerates neurodegeneration

Abstract

Recent evidence suggests that supplemental factors coincident with aging and genetic determinants might be involved in the initial progression of Alzheimer's disease (AD). Early studies also indicate that chronic stress decreases hippocampal neurogenesis. Here, we investigate the effect of chronic stress on hippocampal neurogenesis using a transgenic mouse line (Tg) that overexpresses human presenilin 1 (PS1) with a familial AD (FAD)-related mutation in order to elucidate how the combination of chronic stress and mutated genes affects the cytoarchitecture in the hippocampal granule cell layer (GCL), which contributes to spatial learning and memory. Using an original chronic intermittent restraint stress (CIRS) protocol, we examined the effect of stress on hippocampal neurogenesis and neurodegeneration by immunohistochemical analysis. After short-term CIRS, neurodegeneration in Tg mice was significantly increased in the hippocampus with an earlier onset and progression than in the non-stressed Tg mice. Moreover, after long-term CIRS, transitional neurodegeneration appeared to proceed along the neuronal circuit involved in cognitive function in stressed Tg mice. Although the number of Pax6-positive (+) cells (mostly granule neuron precursors) did not significantly decrease during CIRS in both non-Tg and Tg mice, doublecortin (DCX) + neuronal progenitor cells in the GCL were markedly influenced in Tg mice; they were significantly reduced without stress compared with non-stressed non-Tg mice and significantly increased by CIRS compared with non-stressed Tg mice. We conclude from these results that diverse responses against stressful experiences among genetically predisposed individuals could lead to cognitive dysfunction through retardation of neuronal maturation and neurodegeneration.