Effects of hippocampal aromatase overexpression on spatial learning and memory in APP/PS1 mouse model of Alzheimer's disease and related neural mechanism

Abstract

] Objective To investigate the effects of hippocampal aromatase (AROM) on spatial learning and memory, specific pathology and synaptic plasticity in APP/PS1 mouse model of Alzheimer's disease (AD mice) and explore the underlying mechanisms. Methods Western blotting was used to detect the expression of AROM and androgen receptor in the hippocampus of male WT mice and AD mice at different months of age. Then, an overexpressed viral vector of AROM was constructed (oAROM) and injected stereotaxically into the hippocampus of 6-month-old AD mice. 3 months later, the spatial learning and memory abilities of the mice were studied with Morris water maze test. Western blot was employed to measure the changes of Aβ- and synapse-related proteins, and cytoskeleton regulatory proteins in the hippocampus. Immunohistochemical staining and immunofluorescence assay were used to detect the changes of Aβ. The changes of synaptic density and postsynaptic membrane thickness were observed with transmission electron microscopy. Results The protein level of AROM was significantly decreased in WT mice of 10 months old (P < 0.01), but in the AD mice of only 6 months old (P < 0.01). Compared with the APP/PS1 mice, the time in the target quadrant and the times crossing the platform were significantly increased in the oAROM mice (P < 0.05). In the oAROM mice, the Aβ immunopositive materials were obviously decreased (P < 0.01), levels of Aβ producing protein and actin depolymerization protein were decreased, while Aβ degrading protein, selected synaptic proteins and actin polymerization protein were increased (P < 0.01). Moreover, CA1 synaptic density (P < 0.01) and postsynaptic membrane thickness (P < 0.01) were significantly increased in the oAROM mice. What's more, the expression of actin regulator Profilin-1 was significantly up-regulated (P < 0.01) while Cofilin, a protein controlling dynamics of actin filaments, was significantly decreased (P < 0.01). Conclusion Hippocampus-specific overexpression of AROM can improve the synaptic plasticity and inhibit AD-related pathological changes in the hippocampus of dementia mice, and then improve the spatial learning and memory impairment, suggesting hippocampal AROM may be a novel target against AD.

Keywords

• aromatase
• hippocampus
• learning and memory
• synaptic plasticity
• alzheimer's disease