Mechanisms mediating brain and cognitive reserve: experience-dependent neuroprotection and functional compensation in animal models of neurodegenerative diseases

‘Brain and cognitive reserve’ (BCR) refers here to the accumulated neuroprotective reserve and capacity for functional compensation induced by the chronic enhancement of mental and physical activity. BCR is thought to protect against, and compensate for, a range of different neurodegenerative diseases, as well as other neurological and psychiatric disorders. In this review we will discuss BCR, and its potential mechanisms, in neurodegenerative disorders, with a focus on Huntington's disease (HD) and Alzheimer's disease (AD). Epidemiological studies of AD, and other forms of dementia, provided early evidence for BCR. The first evidence for the beneficial effects of enhanced mental and physical activity, and associated mechanistic insights, in an animal model of neurodegenerative disease was provided by experiments using HD transgenic mice. More recently, experiments on animal models of HD, AD and various other brain disorders have suggested potential molecular and cellular mechanisms underpinning BCR. We propose that sophisticated insight into the processes underlying BCR, and identification of key molecules mediating these beneficial effects, will pave the way for therapeutic advances targeting these currently incurable neurodegenerative diseases.