The effect of dietary fat consumption on Alzheimer’s disease pathogenesis in mouse models

Abstract

Alzheimer’s disease (AD) is a fatal cognitive disorder with proteinaceous brain deposits, neuroinflammation, cerebrovascular dysfunction, and extensive neuronal loss over time. AD is a multifactorial disease, and lifestyle factors, including diet, are likely associated with the development of AD pathology. Since obesity and diabetes are recognized as risk factors for AD, it might be predicted that a high-fat diet (HFD) would worsen AD pathology. However, modeling HFD-induced obesity in AD animal models has yielded inconclusive results. Some studies report a deleterious effect of HFD on Aβ accumulation, neuroinflammation, and cognitive function, while others report that HFD worsens memory without affecting AD brain pathology. Moreover, several studies report no major effect of HFD on AD-related phenotypes in mice, while other studies show that HFD might, in fact, be protective. The lack of a clear association between dietary fat consumption and AD-related pathology and cognitive function in AD mouse models might be explained by experimental variations, including AD mouse model, sex and age of the animals, composition of the HFD, and timeline of HFD consumption. In this review, we summarize recent studies that aimed at elucidating the effect of HFD-induced obesity on AD-related pathology in mice and provide an overview of the factors that may have contributed to the results reported in these studies. Based on the heterogeneity of these animal model studies and given that the human population itself is quite disparate, it is likely that people will benefit most from individualized nutritional plans based on their medical history and clinical profiles.

RETRACTED: Combined metabolic activators improve metabolic functions in the animal models of neurodegenerative diseases

“…Since then, intracerebroventricular injection of STZ has been widely used in animal models to demonstrate impaired neuronal plasticity and learning deficits caused by metabolic diseases [67][68][69]. Moreover, rodent models fed with high-fat diets exhibited all the hallmarks of these degenerative diseases and represented an interesting approach to the study of the phenotypic features and pathogenic mechanisms of NDDs [70,71]. Recently, several genetic models have been suggested with their advantages including capturing both Aβ and phospho-tau as well as maintaining aging features of AD, but high lethality, overexpression of tau protein and limited cognitive impairment were seen in genetic models [72].…”

Detection of early Alzheimer's disease‐like molecular alterations in a mouse model expressing human ApoE4

“…To our knowledge, our study represents the youngest age at which metabolic, gene expression, and AD‐related alterations related to the interplay between ApoE genotype and diet have been reported for rodents. Our findings are consistent with previous studies in humans (Fitzpatrick et al, 2009; Profenno et al, 2010) and rodent models (Barron et al, 2013; Ho et al, 2004; Moser & Pike, 2017) that examined the role of high‐fat‐induced obesity in increasing risk of AD, as well as with previous studies that found APOE4‐expressing mice to be more susceptible to metabolic disturbances, including visceral adipose tissue accumulation and glucose intolerance compared with APOE3‐expressing mice (Amelianchik et al, 2022; Jones et al, 2019).…”

“…A high‐fat diet (HFD), which is closely correlated with obesity (Freeman & Granholm, 2012; Ho et al, 2004), can interact with ApoE status in a manner that elevates the risk of developing AD (Amelianchik et al, 2022; Johnson et al, 2017; Jones & Rebeck, 2019; Mattar et al, 2022; Sullivan et al, 2011; Zhao et al, 2017). In a human ApoE targeted‐replacement mouse model, HFD alters plasma and hippocampal ApoE levels in an ApoE isoform‐dependent manner, reducing hippocampal ApoE levels in ApoE3 targeted‐replacement mice but not in ApoE4 targeted‐replacement mice (Lane‐Donovan & Herz, 2016).…”

New directions for Alzheimer's disease research from the Jackson Laboratory Center for Alzheimer's and Dementia Research 2022 workshop

“…For example, the Mediterranean‐DASH Diet Intervention for Neurodegenerative Delay diet was shown to slow cognitive decline and, with other healthy lifestyle habits, lengthen the health span of individuals in the study with and without AD 20 . The impact of diet on AD pathogenesis is inconsistent across studies, which may be explained by differences in the start and duration of the treatments and in the composition of the diets 21 . To achieve higher rigor and reproducibility, metabolic dietary effects should be assessed by measuring multiple parameters, such as blood glucose, blood pressure, low‐density and high‐density lipoprotein levels, triglyceride levels, and body weight.…”