High Fat Diet Aggravates AD-Related Pathogenic Processes in APP/PS1 Mice

Abstract

Background: Alzheimer’s disease (AD) is the most common neurodegenerative disorder and negative life-style factors may contribute to its etiopathogenesis. Substantial evidence from humans and murine models reveal that Insulin Resistance (IR) associated with high fat diet (HFD) increase the risk of developing AD and age-related amyloidogenesis. Objective: To corroborate and clarify the influence of HFD on amyloidogenesis and cognitive deficits in AD model mice. Results: We here show that a four months HFD-feeding increases IR in both the periphery and brain of APP/PS1 mice, which are used as AD model. Meanwhile, long term HFD exacerbates cognitive defects and impairs dendritic integrity and expressions of synaptic proteins in APP/PS1 mice. Furthermore, HFD induces an increase in β-secretase (BACE1) expression and a decrease in insulin degrading enzyme (IDE) expression, resulting in β-amyloid (Aβ) accumulation. Conclusion: Our data suggests that long term HFD, with the accompanying IR, promotes Aβ toxicity and cognitive deficits, indicating that modifiable life-style hazards such as HFD-induced IR might contribute to AD pathogenesis.

Long-Term High-Fat Diet Consumption Induces Cognitive Decline Accompanied by Tau Hyper-Phosphorylation and Microglial Activation in Aging

“…Walker et al reported ten-month HFD treatment increased the level of tau phosphorylation in the hippocampus of AD model mice [ 40 ]. Gong et al also found that four-month HFD feeding for AD model mice increased insulin resistance and β-amyloid accumulation which is another pathological hallmark of AD [ 41 ]. Accumulating studies indicate that obese elderly people exhibit an increase in tau phosphorylation of the hippocampus.…”

In Vivo Reductionist Approach Identifies miR-15a Protecting Mice From Obesity

“…Moreover, obesity or hyperglycaemia can cause up-regulation of hepatic expression of the immature form of Bace1 that is implicated in insulin receptor shedding ( 36 ). Furthermore, long-term exposure to high-fat diet increases Bace1 expression in the brain promoting β-amyloid (Aβ) accumulation and cognitive deficits ( 37 ), while treatment with Bace1 inhibitor reduces circulating levels of Aβ 1-42 peptide ( 38 ) in high-fat diet-induced obese mice. In the brain, Bace1 is expressed in the cortex, hippocampus ( 39 ) and the hypothalamus including ARH ( 26 ).…”

Long‐Term High‐Fat Diet Consumption Aggravates β‐Amyloid Deposition and Tau Pathology Accompanied by Microglial Activation in an Alzheimer's Disease Model

“…[1] AD is highly heterogeneous, which is related to multitude of genetic and environmental factors. [2,3] While advanced age (beyond 65 years) and genetic predisposition (APOE 𝜖4 allele) are the principal risk factors for AD, a variety of etiological factors, such as obesity, diabetes, and long-term consumption of high-fat diet (HFD), [4][5][6] have also been postulated to contribute to cognitive deficits and escalate AD susceptibility. [7] Epidemiological research has indicated that consuming a significant amount of saturated fat for a duration of 4-6 years (particularly during middle age) poses a substantial threat in terms of the likelihood of developing mild cognitive impairment and dementia in individuals aged 65 and above, a jeopardy that is further compounded in the presence of the APOE 𝜖4 allele.…”