Mechanisms of estrogen deficiency-induced inflammatory reaction aggravation in the brain of dementia mice

LUO Min; JIANG Tingting; DU Yexiang; WANG Kejian; HE Guiqiong

doi:10.13431/j.cnki.immunol.j.20190057

Abstract：To clarify the molecular mechanisms of estrogen deficiency-induced inflammatory reaction aggravation in brain of mice with dementia, we investigate the changes of mitochondrial structure, mitochondrialestrogen receptor β (mt-ERβ), insulin-like growth factor 1 receptor (IGF-1 R), astrocyte (AS) andneuroinflammation factors in the brain of APP/PS1 double transgenic mice. Female 3-month-old APP/PS1 double transgenic AD mice underwent bilateralovariectomy (AD-OVX) were set as experiment group, while sham-operated AD mice (AD-sham) and wild-type mice (WT) of the same age were used as controls. Immunofluorescence, RT-PCR, transmission electronmicroscopy and Western blot (WB) were used to detect the changes of glial fibrillary acidic protein (GFAP), inflammatory factors (IL-6 and TNF-α), mitochondrial ultrastructure, mt-ERβ and IGF-1 R at week 1 (simulating earlymenopause) and month 3 (simulating middle and late menopause) post-surgery. Compared with wild-type mice, thenumber of GFAP-positive cells in the brain of AD-OVX group and AD-sham group was increased significantly in 1 week or 3 months after OVX, and correspondingly, the mRNA levels of IL-6 and TNF-α were also increasedsignificantly (P<0.001); the mitochondrial swelling was evident in AD brain, while mt-ERβ and IGF-1 Rexpressions demonstrated a downward trend (P<0.001); the number of GFAP positive cells in AD-OVX group wassignificantly lower than that of AD-Sham group at 1 week after OVX (P<0.001), and the mRNA levels of IL-6 andTNF-α were decreased significantly in AD-OVX group (P<0.001), but there were no significant difference inmitochondrial structure, mt-ERβ and IGF-1 R protein expression (P>0.05). However, 3 months after OVX, thenumber of GFAP-positive cells in AD-OVX group was higher than that in AD-sham group (P<0.001), and theinflammatory factors were increased significantly (P<0.001), the mitochondrial swelling was obvious, the expressionof mt-ERβ was up-regulated (P<0.05), and the expression of IGF-1 R was decreased significantly (P<0.05). Inconclusion, early estrogen deficiency reduces the proliferation of astrocytes and the inflammation reactivity in thebrain of dementia mice, but with the prolongation of estrogen deficiency, the activation of astrocytes andneuroinflammatory response are progressively aggravated. This effect may be related to the mt-ERβ mediated IGF-1 R signaling pathway.