Department of Integrative Neuroscience, National Center for Geriatrics and Gerontology, Aichi, Japan.
Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Saitama, Japan.
Neuropsychopharmacol Rep. 2022 Sep;42(3):272-280. doi: 10.1002/npr2.12257. Epub 2022 May 18.
Type 2 diabetes mellitus (T2DM) is an increased risk factor for Alzheimer's disease (AD); however, the relationship between the 2 conditions is controversial. High-fat diet (HFD) causes cognitive impairment with/without Aβ accumulation in middle-aged or aged transgenic (Tg) and knock-in (KI) AD mouse models, except for metabolic disorders, which commonly occur in all mice types. Alternatively, whether HFD in early life has an impact on nutrient metabolism and neurological phenotypes in young AD mouse models is not known. In the present study, we examined the effects of HFD on young APPKI mice, one of the novel KI-AD mouse models.
The mice were categorized by diet into 2 experimental groups, normal diet (ND) and HFD. Four-week-old wild-type (WT) and APPKI mice were fed ND or HFD for 9 weeks. Both types of mice on ND and HFD were examined during young adulthood.
HFD caused T2DM-related metabolic disturbances in both young WT and APPKI mice, whereas impaired thermoregulation and shortage of alternative energy sources specifically occurred in young APPKI mice. However, HFD had no impact on the cognitive function, Aβ levels, and phosphorylation of hippocampal insulin receptor substrate 1 (IRS1) at all the 3 Ser sites in both types of mice.
HFD is effective in causing metabolic disturbances in young WT and APPKI mice but is ineffective in inducing neurological disorders in both types of mice, suggesting that the aging effects, along with long-term HFD, facilitate neurological alterations.
2 型糖尿病（T2DM）是阿尔茨海默病（AD）的一个危险因素增加；然而，这两种情况之间的关系是有争议的。高脂肪饮食（HFD）会导致认知障碍，伴有/不伴有 Aβ 积累，在中年或老年转基因（Tg）和敲入（KI）AD 小鼠模型中，但不包括代谢紊乱，这在所有小鼠类型中都很常见。相反，在年轻的 AD 小鼠模型中，早期生命中的 HFD 是否会对营养代谢和神经表型产生影响尚不清楚。在本研究中，我们研究了 HFD 对年轻 APPKI 小鼠的影响，这是一种新型 KI-AD 小鼠模型之一。
根据饮食将小鼠分为 2 个实验组，正常饮食（ND）和 HFD。4 周龄野生型（WT）和 APPKI 小鼠分别用 ND 或 HFD 喂养 9 周。在年轻成年期检查了 ND 和 HFD 组的两种类型的小鼠。
HFD 导致年轻 WT 和 APPKI 小鼠的 T2DM 相关代谢紊乱，而热调节受损和替代能源短缺仅发生在年轻的 APPKI 小鼠中。然而，HFD 对两种类型的小鼠的认知功能、Aβ 水平和海马胰岛素受体底物 1（IRS1）的 3 个丝氨酸位点的磷酸化均没有影响。
HFD 有效地导致年轻 WT 和 APPKI 小鼠的代谢紊乱，但不能诱导两种类型的小鼠的神经紊乱，这表明衰老效应，加上长期的 HFD，促进了神经改变。
