Senescence and unhealthy diet tied to Alzheimer’s disease in mice

Naveed Saleh, MD, MS, for MDLinx | August 02, 2018

Along with the normal aging process, a high-fat high-sucrose diet (HFS) in mice may play a contributory role in Alzheimer’s disease (AD), as evidenced by various biomarkers, according to a new study in Physiological Reports.

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In mice, researchers have shown that aging combined with a high fat, high sugar diet can cause increased inflammation and stress in both the hippocampus and prefrontal cortex, and possibly contribute to the development of Alzheimer’s disease.

“This study provides novel information in relation to the mechanistic link between obesity and the transition from adulthood into middle age and signaling cascades that may be related to AD pathology later in life,” wrote authors, led by Rebecca E. K. MacPherson, PhD, assistant professor, Department of Health Sciences, Brock University, St. Catharines, Ontario, Canada.

Although senescence is the single biggest risk factor in the pathogenesis of AD, obesogenic diet has been fingered as contributory, too. In light of a paucity of AD treatments, viewing this disease in metabolic terms could be helpful.

Two histopathologic attributes typify AD: (1) the accumulation of beta-amyloid protein (Aβ) plaques and (2) hyper-phosphorylated tau tangles. Experts have linked obesity secondary to diet to the amplification of Aβ production. Although previous research has shown that obesity can lead to ADesque pathology, this research has examined obesity effects at different ages, but foundational mechanisms—especially early ones—have yet to be elucidated.

Aβ arises from a large type 1 transmembrane protein called amyloid precursor protein (APP). Furthermore, the β-secretase pathway is commenced by beta-site amyloid precursor protein cleaving enzyme 1 (BACE1).

“Alterations in inflammatory/cellular stress pathways (mitogen-activated protein kinases, MAPK), insulin signaling, and markers of energetic stress (50 adenosine monophosphate–activated protein kinase, AMPK) have all been implicated in AD and the amyloidogenic pathway,” the researchers wrote.

MAPKs are serine-threonine kinases that facilitate cellular signaling linked to a gamut of cellular activities, including cell proliferation, differentiation, survival, and apoptosis. MAPK pathways are triggered by extra- and intracellular stimuli associated with stress and include extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK).

Experts suggest that various mechanisms underlie the relationship between MAPK pathways and AD pathogenesis, such as neuronal apoptosis, increased BACE1 expression, and the phosphorylation of APP by JNK. To date, the few studies tying brain MAPK pathways to obesity are scarce and have yielded mixed results.

Diets resulting in obesity commonly yield insulin resistance and energetic stress in peripheral tissues. Furthermore, obesity changes insulin signaling in the brain and, thus, energy status. More specifically, abnormal maintenance of insulin signaling via PI3-kinase and protein kinase B (Akt) has been evidenced in brain tissue from patients with AD, in addition to being evidenced in brains from animal models of diet-induced obesity.

In samples from people with AD, experts have noted heightened Akt phosphorylation with significant increases in the phosphorylation of many Akt substrates, such as glycogen synthase kinase (GSK). Notably, GSK has been connected to AD progression.

Brain samples from AD patients have exhibited abnormally activated AMPK, which experts consider a marker of disturbed brain energy metabolism. Nevertheless, the effects of aging and diet on AMPK activity in the brain have yet to be elucidated.

In the current study, Dr. MacPherson and co-authors analyzed changes in markers of inflammation and cellular stress, insulin signaling, and energetic stress in adult male mice as they advance to middle age, while consuming an HFS, or obesogenic, diet. They hypothesized that this diet would worsen the effects of senescence on the metabolic pathways related to the advance of AD.

The investigators randomized 12 mice to a control diet and 12 mice to an HFS diet and administered both diets between age 20 and 33 weeks. They collected prefrontal and hippocampal samples from these mice at age 33 weeks. In a baseline group of 11 mice, the team procured prefrontal and hippocampal samples at 20 weeks.

The HFS diet in aged mice caused significant increases in body weight (30%; P=0.0001) and percentage fat mass (28%; P=0.0001), as well as a significant percentage decrease in lean mass (33%; P=0.0001) compared with these measures in aged mice on the control diet.

The researchers found that transitioning to middle age yielded increased hippocampal JNK and Akt Ser473 phosphorylation in aged mice. Aging while on the HFS diet, however, resulted in even higher hippocampal JNK and Akt Ser473 phosphorylation than did aging on a control diet, as well as increased ERK and GSK-3b phosphorylation in the hippocampus. Moreover, the HFS diet in aged mice caused heightened AMPK phosphorylation in the prefrontal cortex.

“These results highlight neuroinflammation/stress, altered brain insulin signaling, and increased energetic stress as important brain alterations with diet-induced obesity in middle age,” the authors wrote.

Of interest, the authors found that changes in the prefrontal cortex and hippocampus secondary to aging and an HFS diet were disparate.

“Results from this study demonstrate that aging combined with a HFS diet results in increased inflammation (pERK and pJNK) and energetic stress (pAMPK) in the hippocampus and prefrontal cortex, respectively,” the authors concluded. “Together these novel results provide important information for future targets in early AD pathogenesis.”

This study was funded by the Natural Sciences and Engineering Research Council of Canada and the Canadian Foundation for Innovation.

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