Alzheimer’s disease : high maternal fat consumption during gestation protects offspring against changes in the brain

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Regions of interest were drawn in frontal, parietal, occipital, right/left temporal cortices, cerebellum, brainstem and whole brain (a). Representative sagittal images document a higher GU at birth and deficiency thereafter in the offspring of HFD than ND mothers (b).

A high-fat diet can carry health risks, but for mothers-to-be, it may make all the difference when it comes to Alzheimer’s disease prevention for their children.

In a report published online August 26 in the journal Molecular Psychiatry, researchers at the Lewis Katz School of Medicine at Temple University show for the first time in animals that high maternal fat consumption during gestation protects offspring against changes in the brain that are characteristic of late-onset Alzheimer’s disease.

“In humans, it has been known that individuals whose mothers develop Alzheimer’s disease after age 65 are at increased risk of also developing the disease around the same age,” said senior investigator Domenico Praticò, MD, Scott Richards North Star Foundation Chair for Alzheimer’s Research, Professor in the Departments of Pharmacology and Microbiology, and Director of the Alzheimer’s Center at Temple at the Lewis Katz School of Medicine.

Genetic factors transmitted by mothers to their offspring seem like an obvious explanation behind this phenomenon, but so far no genes have been identified that could explain the maternal transmission of Alzheimer’s disease.

This fact would suggest that environmental factors, such as lifestyle and diet, adopted during the gestation period, a time in which mother and baby are in tight interaction, could significantly influence the offspring’s risk of developing the disease later in life.

Diet is of particular interest as a risk factor, especially a diet rich in animal fat and cholesterol.

High-fat intake previously has been shown in young/adult mice to directly exacerbate the types of changes in brain function that ultimately may contribute to Alzheimer’s disease.

To better understand the unique relationship between maternal Alzheimer’s disease and risk in her offspring, Dr. Praticò and colleagues looked at maternal fat intake specifically during the gestation period in mice engineered to develop Alzheimer’s disease.

Pregnant mice were fed a high-fat diet from the beginning until the end of gestation.

The moment offspring were born, mothers were switched to a regular diet, which was maintained during the lactation period.

Offspring of these mothers were always kept at the same regular, or standard, diet throughout their life.

At 11 months of age, offspring underwent behavioral tests to assess learning ability and memory.

“Surprisingly, we found that animals from mothers fed a high-fat diet during gestation had better learning and memory skills than their counterparts born to mothers fed a regular diet during gestation,” Dr. Praticò said.

The observed improvements in memory and learning were associated with the maintenance of good synaptic integrity.

In fact, offspring from mothers exposed to a high-fat diet had significant improvement of synapse function when compared with offspring from mothers on a regular diet.

Synapses, the places where neurons come together to relay information, play a vital role in learning and memory formation.

In addition, compared to animals born to mothers fed a regular diet, offspring from mothers on a high-fat diet had lower levels of amyloid-beta, an abnormal protein that builds up in neurons, contributing to nerve cell dysfunction and eventually significant impairments in memory and learning

When the team searched for possible mechanisms responsible for the beneficial effect, they discovered that offspring from mothers fed a high-fat diet exhibited reduced levels of three important genes involved in Alzheimer’s disease:

beta-secretase,

tau,

and the pathological tau-regulating gene CDK5.

Dr. Praticò’s team found that already in the early developmental stages, the three genes were effectively switched off in offspring because the high-fat diet had increased activity of a protein called FOXP2.

They demonstrated that the repressive activity of FOXP2 on these genes ultimately protected offspring from later declines in brain function and Alzheimer’s disease development.

“Our findings suggest that, to be effective, Alzheimer’s disease prevention probably needs to start very early in life, during gestation,” Dr. Praticò said. “Diet at this specific life stage can have critical, but underestimated, long-term impacts on brain health.”

Dr. Praticò and colleagues plan next to compare the effects of a high-fat diet to those of other diets, including diets high in sugar and protein and diets resembling the Mediterranean diet in humans.

“We also want to see whether our findings can be replicated in wild-type animals” Dr. Praticò added.


Maternal nutrition during pregnancy and lactation influence the health of mother and child (1).

Maternal high-fat diet (HFD) is linked to the high risk of developing metabolic disorders including chronic liver disease, diabetes, high blood pressure, and obesity in offspring (23).

Maternal diet can also alter offspring behaviors and cognitive abilities by modifying the intrauterine environment and maternal behaviors (45).

Offspring of obese mothers consuming HFD are vulnerable to mental and behavioral disorders including depression, anxiety, attention deficit hyperactivity disorder, and autism (56).

A possible mechanism of increased risk for behavioral disorders is alterations in neural pathways development involved in behavioral regulation (3).

It has also been reported that intake of HFD during pregnancy is associated with learning impairments and memory loss in the adult offspring (67).

Exact mechanisms explaining the link between HFD during pregnancy and memory disorders in infants are not known.

Recent findings indicate factors such as the type of nutrient intake (sugar and fat), hormones (insulin and leptin), and inflammatory cytokines affect fetal brain development (3).

Development of neurotransmitter systems is also influenced by the levels of circulating cytokines (89).

Cytokines also have direct detrimental effects on hippocampal circuitry and cognition (10).

Apelin, as an adipokine, is secreted by adipocytes.

It was initially isolated in 1998 from bovine stomach and defined as an endogenous ligand for an orphan G-protein coupled receptor, APJ (11).

Apelin and its receptors are broadly distributed in the peripheral tissues and central nervous system (CNS) particularly in the hippocampus and amygdala, brain regions involved in learning and memory, and hypothalamus (1113).

Expression of apelin is influenced by nutritional status and decreased by fasting and recovered by refeeding (14).

Apelin is considered as an anti-obesity peptide which increases the sensitivity of various tissues especially skeletal muscles to insulin, enhances energy consumption, and reduces body fat mass (1516).

Moreover, apelin has important roles in the regulation of immune response (17), hemodynamic and body fluid homeostasis, angiogenesis, oxidative stress-linked atherosclerosis, and brain signaling (18).

It is also reported that apelin is involved in the regulation of memory formation (1920), and its active form protects the nervous system from different diseases such as Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease (21).

Troxerutin, a natural bioflavonoid rutin, is present in tea, coffee, cereal grains, and different types of fruits and vegetables (22).

Previous studies revealed that it has multiple biological properties including anti-neoplastic, antioxidant, and anti-inflammatory effects (2225).

Our previous studies demonstrated that troxerutin reduces oxidative stress markers, improves spatial learning and memory, and ameliorates synaptic plasticity of dentate gyrus neurons in an amyloid-beta induced rat model of Alzheimer’s disease (2628).

To better understand the impact of maternal HFD on offspring behavior, the effect of troxerutin treatment on HFD-induced spatial learning and memory impairments, as well as serum and hippocampal apelin levels in offspring was evaluated.


More information: Antonio Di Meco et al, Gestational high fat diet protects 3xTg offspring from memory impairments, synaptic dysfunction, and brain pathology, Molecular Psychiatry (2019). DOI: 10.1038/s41380-019-0489-y

Journal information: Molecular Psychiatry
Provided by Temple University

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