High-fat diet exacerbates cognitive decline in mouse models of Alzheimer's disease and mixed dementia in a sex-dependent manner

Abstract

Background Approximately 70% of Alzheimer’s disease (AD) patients have co-morbid vascular contributions to cognitive impairment and dementia (VCID); this highly prevalent overlap of dementia subtypes is known as mixed dementia (MxD). AD is more prevalent in women, while VCID is slightly more prevalent in men. Sex differences in risk factors may contribute to sex differences in dementia subtypes. Unlike metabolically healthy women, diabetic women are more likely to develop VCID than diabetic men. Prediabetes is 3× more prevalent than diabetes and is linked to earlier onset of dementia in women, but not men. How prediabetes influences underlying pathology and cognitive outcomes across different dementia subtypes is unknown. To fill this gap in knowledge, we investigated the impact of diet-induced prediabetes and biological sex on cognitive function and neuropathology in mouse models of AD and MxD. Methods Male and female 3xTg-AD mice received a sham (AD model) or unilateral common carotid artery occlusion surgery to induce chronic cerebral hypoperfusion (MxD model). Mice were fed a control or high fat (HF; 60% fat) diet from 3 to 7 months of age. In both sexes, HF diet elicited a prediabetic phenotype (impaired glucose tolerance) and weight gain. Results In females, but not males, metabolic consequences of a HF diet were more severe in AD or MxD mice compared to WT. In both sexes, HF-fed AD or MxD mice displayed deficits in spatial memory in the Morris water maze (MWM). In females, but not males, HF-fed AD and MxD mice also displayed impaired spatial learning in the MWM. In females, but not males, AD or MxD caused deficits in activities of daily living, regardless of diet. Astrogliosis was more severe in AD and MxD females compared to males. Further, AD/MxD females had more amyloid beta plaques and hippocampal levels of insoluble amyloid beta 40 and 42 than AD/MxD males. In females, but not males, more severe glucose intolerance (prediabetes) was correlated with increased hippocampal microgliosis. Conclusions High-fat diet had a wider array of metabolic, cognitive, and neuropathological consequences in AD and MxD females compared to males. These findings shed light on potential underlying mechanisms by which prediabetes may lead to earlier dementia onset in women.

cGAS/STING and innate brain inflammation following acute high-fat feeding

“…Additionally, there are known differences between males and females in terms of immune function and inflammation ( 81 , 82 ), including in microglia ( 83 ). These differential effects also potentially impact cognition, as some have shown a differential effect of sex on cognitive outcomes ( 84 ). As mentioned above, no differences were observed between groups for puzzle box performance.…”

Trends in Gliosis in Obesity, and the Role of Antioxidants as a Therapeutic Alternative

“…The prevention, diagnosis and treatment of gliosis must be addressed in patients with obesity, and especially in those who have metabolic comorbidities, points included in this review. Gliosis, if left untreated, can increase the risk of long-term neurodegeneration [ 5 ]. The pathophysiology of gliosis includes the increase in free radicals, which perpetuate neuroinflammation [ 6 ].…”

Obese mice induced by high-fat diet have differential expression of circular RNAs involved in endoplasmic reticulum stress and neuronal synaptic plasticity of hippocampus leading to obesity-associated cognitive impairment

“…It has been accepted that the hippocampus is the main functional area responsible for learning and memory; hippocampus dysfunction is considered to be a key and central mechanism that underlies cognitive impairment (Gannon et al, 2022 ). Of course, neuronal synaptic plasticity has long been considered an important component and the neural basis of learning and memory (Neves et al, 2008 ), and it has been reported that HFD can damage the synaptic plasticity in the hippocampal neurons of obese mice (O'Brien et al, 2017 ).…”