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

Abstract

‘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.

Introduction

A theory of ‘brain reserve’ has been developed to conceptualise the neuroprotective brain capacity that can be induced when mental, as well as physical, activity chronically enhanced (Katzman, 1993, Satz et al., 1993, Stern et al., 1995, Mortimer, 1997, Schmand et al., 1997, Valenzuela and Sachdev, 2006a, Valenzuela and Sachdev, 2006b; reviewed by Valenzuela, 2008). The associated term ‘cognitive reserve’ was originally used to help explain epidemiological data which suggested that increased cognitive function and enhanced complex mental activity provided a functional reserve that could compensate for the pathogenic processes associated with brain disorders such as AD and dementia (Graves et al., 1996, Stern, 2002, Scarmeas and Stern, 2003, Stern et al., 2003, Scarmeas and Stern, 2004, Whalley et al., 2004, Le Carret et al., 2005, Mortimer et al., 2005, Richards and Deary, 2005, Stern et al., 2005, Andel et al., 2006; reviewed by Stern, 2009). The terms have often been used somewhat interchangeably, as it is difficult to distinguish reserves at the level of brain or cognition, and therefore it is simpler to refer to these ideas collectively as a broad theory of ‘brain and cognitive reserve’ (BCR; Nithianantharajah and Hannan, 2009).

BCR may provide neuroprotective and compensatory capacities not only for AD and dementia, but also a wide range of other brain disorders (reviewed by Nithianantharajah and Hannan, 2009). The neurobiology of BCR has been informed by environmental manipulations of animal models. Environmental enrichment, which enhances mental and physical activity levels, has been found to induce beneficial effects in rodent models of neurodegenerative diseases including HD (van Dellen et al., 2000, Hockly et al., 2002), AD (Levi et al., 2003, Arendash et al., 2004, Jankowsky et al., 2005, Lazarov et al., 2005), Parkinson's disease (Bezard et al., 2003, Faherty et al., 2005), amyotrophic lateral sclerosis (Stam et al., 2008) and multiple sclerosis (Magalon et al., 2007). However, the scope of this article will be restricted to BCR and specific neurodegenerative brain diseases, with HD and AD used as key examples. While we will touch on the epidemiology and clinical data, which has recently been reviewed elsewhere (e.g. Valenzuela et al., 2007, Valenzuela, 2008), the main focus will be on evidence for BCR, and its underlying mechanisms, in animal models of HD and AD.