Does maternal high fat diet lead to dementia?

Roxana Carare MD, PhD, Professor of Clinical Neuroanatomy

Alzheimer’s disease is the most common form of dementia, with no efficient treatment available to slow down or cure the disease. Identifying factors that could be addressed in the prevention of the disease is urgent. One of the key elements in Alzheimer’s disease is the failure of elimination of fluid and amyloid from the brain ¹. We have demonstrated that elimination of fluid and soluble metabolites such as amyloid occurs along the basement membranes of capillaries and arteries against the direction of blood flow, towards the surface of the brain, as intramural periarterial drainage (IPAD) ². This process fails with increasing age, with possession of Apolipoprotein E4 genotype and hyperlipidemia ^3-5. We have demonstrated that a diet rich in fat during pregnancy and lactation results in modifications of the components of the vessel walls and failure of the drainage of amyloid in the young adult offspring mice ^5,6. Thus, there appears to be some developmental programming effect of high fat diet-induced maternal obesity during pregnancy and lactation that leads to increased failure of eliminating amyloid from the brain. These findings in mice may have serious implication in humans, with almost 20% of all pregnancies complicated by obesity due to consumption of fat-rich diet. Current intervention strategies to reduced risk associated with developmental programming of diseases in the offspring in later life include the use of the anti-diabetic drug metformin in treating obese pregnant mothers. Unpublished data from the current applicants has shown that maternal metformin treatment in obese pregnant mice protects the 30 week-old female offspring, but not the male offspring, from developing diabetes when put on an obesogenic high fat diet. It is not known whether this protective effect of maternal metformin treatment in obese pregnancy could also prevent or reduced the modifications of the vessel walls and failure of the drainage of amyloid in the brain of young and ageing offspring. Resolving these questions is the focus of the present work. In order to fulfil the aim of the project, we will establish the colonies with the different groups of mice based on diet and metformin treatment. Brains will be processed for electron microscopy, proteomic and epigenetic studies.

Summary of experimental design

References

1. Tarasoff-Conway, J.M., et al. Clearance systems in the brain-implications for Alzheimer diseaser. Nature reviews. Neurology 12, 248 (2016).
2. Carare, R.O., et al. Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology. Neuropathol.Appl.Neurobiol. 34, 131-144 (2008).
3. Hawkes, C.A., et al. Perivascular drainage of solutes is impaired in the ageing mouse brain and in the presence of cerebral amyloid angiopathy. Acta neuropathologica 121, 431-443 (2011).
4. Hawkes, C.A., et al. Disruption of arterial perivascular drainage of amyloid-beta from the brains of mice expressing the human APOE epsilon4 allele. PloS one 7, e41636 (2012).
5. Hawkes, C.A., Gentleman, S.M., Nicoll, J.A. & Carare, R.O. Prenatal high-fat diet alters the cerebrovasculature and clearance of beta-amyloid in adult offspring. The Journal of pathology 235, 619-631 (2015).
6. Manousopoulou, A., et al. Are you also what your mother eats? Distinct proteomic portrait as a result of maternal high-fat diet in the cerebral cortex of the adult mouse. Int J Obes (Lond) (2015).