As the brain ages it takes on a pro-inflammatory profile associated with priming of immune cells so that they become hyper-active. Aged individuals, even otherwise healthy ones, therefore respond to illness and infection with exaggerated immune responses that can be fatal. The brain’s immune cells in ageing people are also more active under basal conditions, potentially resulting in excess pruning of neuronal synapses and even excess neuronal death. In this way, this neuroinflammatory ageing also contributes to cognitive decline.
Chronic central inflammation that commences earlier in life may trigger early neuroinflammatory ageing and contribute to impaired brain function, including impaired cognition, prior to old-age and may accelerate the onset of dementia. The chronic central inflammation associated with obesity is one such potential trigger.
We, and others, have shown high fat diet can lead to brain inflammation with priming of the brain’s immune cells to be more reactive to neuroimmune challenge. We therefore hypothesize that obesity leads to brain inflammation that primes microglia to retain a pro-inflammatory or ‘activated’ state similar to that seen in the aged individual. These primed microglia will be hyper-active and will lead to brain cell remodeling to the detriment of cognitive function.
Here we aim to:
1) Determine if obesity leads to accelelerated neuroinflammatory ageing in a rodent model and if this is linked to cognitive dysfunction.
2) Identify blood biomarkers in the rodent model that reflect degree of brain inflammation.
3) Establish if blood biomarkers of brain inflammation and cognitive dysfunction identified in the rat also predict degree of cognitive dysfunction and onset of dementia in ageing humans.