Norwich Medical School, University of East Anglia, Norwich, UK.
FASEB J. 2021 May;35(5):e21583. doi: 10.1096/fj.202002621RR.
The impact of sex and menopausal status in Alzheimer's disease remains understudied despite increasing evidence of greater female risk, particularly in APOE4 carriers. Utilizing female APOE-TR mice maintained on a high-fat diet background we induced ovarian failure through repeated VCD injections, to mimic human menopause. At 12 months of age, recognition memory and spatial memory were assessed using object recognition, Y-maze spontaneous alternation, and Barnes maze. A VCDgenotype interaction reduced the recognition memory (P < .05), with APOE4 VCD-treated animals unable to distinguish between novel and familiar objects. APOE4 mice displayed an additional 37% and 12% reduction in Barnes (P < .01) and Y-maze (P < .01) performance, indicative of genotype-specific spatial memory impairment. Molecular analysis indicated both VCD and genotype-related deficits in synaptic plasticity with BDNF, Akt, mTOR, and ERK signaling compromised. Subsequent reductions in the transcription factors Creb1 and Atf4 were also evident. Furthermore, the VCDgenotype interaction specifically diminished Ephb2 expression, while Fos, and Cnr1 expression reduced as a consequence of APOE4 genotype. Brain DHA levels were 13% lower in VCD-treated animals independent of genotype. Consistent with this, we detected alterations in the expression of the DHA transporters Acsl6 and Fatp4. Our results indicate that the combination of ovarian failure and APOE4 leads to an exacerbation of cognitive and neurological deficits.
尽管越来越多的证据表明女性风险更高，尤其是在 APOE4 携带者中，但性别和绝经状态对阿尔茨海默病的影响仍研究不足。利用在高脂肪饮食背景下维持的雌性 APOE-TR 小鼠，我们通过反复注射 VCD 来诱导卵巢衰竭，以模拟人类绝经。在 12 个月大时，使用物体识别、Y 迷宫自发交替和 Barnes 迷宫评估识别记忆和空间记忆。VCD基因型相互作用降低了识别记忆（P<.05），APOE4 VCD 处理的动物无法区分新物体和熟悉物体。APOE4 小鼠在 Barnes（P<.01）和 Y 迷宫（P<.01）的表现中额外降低了 37%和 12%，表明存在与基因型特异性空间记忆损伤相关的缺陷。分子分析表明，VCD 和基因型相关的突触可塑性缺陷与 BDNF、Akt、mTOR 和 ERK 信号受损有关。随后，Creb1 和 Atf4 的转录因子也明显减少。此外，VCD基因型相互作用特异性降低了 Ephb2 的表达，而 Fos 和 Cnr1 的表达则由于 APOE4 基因型而降低。无论基因型如何，VCD 处理动物的大脑 DHA 水平降低了 13%。与此一致，我们检测到 DHA 转运蛋白 Acsl6 和 Fatp4 的表达发生了改变。我们的结果表明，卵巢衰竭和 APOE4 的结合导致认知和神经功能缺陷加剧。
