Mid‐life environmental enrichment increases synaptic density in CA1 in a mouse model of Aβ‐associated pathology and positively influences synaptic and cognitive health in healthy ageing
There is a wealth of evidence supporting EE‐induced cognitive and neural benefit in a range of animal models of neurodegenerative disease (Nithianantharajah & Hannan, 2006). However, the reported effects on a hallmark pathological feature of AD, Aβ plaques, in familial Alzheimer's disease (FAD) animal models have been variable. Following an EE intervention, reduction (Costa et al., 2007; Herring et al., 2011; Lazarov et al., 2005), no change (Arendash et al., 2004; Cotel, Jawhar, Christensen, Bayer, & Wirths 2012; Wolf et al., 2006), or an exacerbation of Aβ pathological burden (Jankowsky, Xu, Fromholt, Gonzales & Borchelt, 2003; Jankowsky et al., 2005) has been reported in transgenic mice expressing human FAD‐related gene mutations. Notably, many of these EE studies have involved such stimulation (EE) from weaning or in early life. Despite the variation between studies regarding Aβ pathological alterations following EE, there is a consensus of marked protection of cognitive function following this intervention.
In this regard, the underlying mechanism allowing for cognitive protection is elusive. EE in other models may influence synaptic connectivity in order to provide cognitive benefit (Nithianantharajah & Hannan, 2006). Moreover, brain‐derived neurotrophic factor (BDNF), a protein expressed widely throughout the central nervous system, vital for the maintenance, survival, and growth of neurons (Mattson, Maudsley, & Martin, 2004) has been implicated in both AD and EE. As BDNF mediates synaptic plasticity and cognitive function (e.g., Lu, 2003; Murer, Yan, & Raisman‐Vozari, 2001), it is thought that BDNF may be critically involved in the pathophysiology underlying cognitive decline in AD. Moreover, reduced levels of BDNF are found in the hippocampus and frontal and parietal cortices of the AD brain (Ferrer et al., 1999; Hock, Heese, Hulette, Rosenberg, & Otten, 2000). BDNF promotes synapse formation (Park & Poo, 2013) and thus could be a potential target for diseases of synaptic plasticity failure, such as in AD. To date, BDNF has not been able to be delivered across the blood‐brain barrier (Lu, Nagappan, Guan, Nathan, & Wren, 2013). However, some evidence suggests EE may be able to increase endogenous levels of BDNF in healthy animals (Ickes et al., 2000; Novkovic, Mittmann, & Manahan‐Vaughan, 2015; Ramírez‐Rodríguez et al., 2014).
With respect to human interventions of relevance to dementia and EE, the benefit of early‐life cognitive stimulation, in the form of education, on later‐life cognitive function has been well reported (e.g., Anstey & Christensen, 2000; Lenehan, Summers, Saunders, Summers, & Vickers, 2014). However, research on the potential protective effects of later‐life cognitive engagement and enrichment is limited. The Tasmanian Healthy Brain Project (THBP; Summers et al., 2013) has produced the first research on the potential benefit of formal late‐life education on cognitive reserve (Lenehan et al., 2015). However, investigation of later‐life EE in animal models of neuropathology has been limited. Moreover, whether cognitive intervention introduced at the inception of AD‐neuropathology produces benefit is unknown.