Exercise-induced cognitive plasticity, implications for mild cognitive impairment and Alzheimer's disease

Abstract

Lifestyle factors such as intellectual stimulation, cognitive and social engagement, nutrition, and various types of exercise appear to reduce the risk for common age-associated disorders such as Alzheimer's disease (AD) and vascular dementia. In fact, many studies have suggested that promoting physical activity can have a protective effect against cognitive deterioration later in life. Slowing or a deterioration of walking speed is associated with a poor performance in tests assessing psychomotor speed and verbal fluency in elderly individuals. Fitness training influences a wide range of cognitive processes, and the largest positive impact observed is for executive (a.k.a. frontal lobe) functions. Studies show that exercise improves additional cognitive functions such as tasks mediated by the hippocampus, and result in major changes in plasticity in the hippocampus. Interestingly, this exercise-induced plasticity is also pronounced in APOE ε4 carriers who express a risk factor for late-onset AD that may modulate the effect of treatments. Based on AD staging by Braak and Braak (1991) and Braak et al. (1993) we propose that the effects of exercise occur in two temporo-spatial continua of events. The "inward" continuum from isocortex (neocortex) to entorhinal cortex/hippocampus for amyloidosis and a reciprocal "outward" continuum for neurofibrillary alterations. The exercise-induced hypertrophy of the hippocampus at the core of these continua is evaluated in terms of potential for prevention to stave off neuronal degeneration. Exercise-induced production of growth factors such as the brain-derived neurotrophic factor (BDNF) has been shown to enhance neurogenesis and to play a key role in positive cognitive effects. Insulin-like growth factor (IGF-1) may mediate the exercise-induced response to exercise on BDNF, neurogenesis, and cognitive performance. It is also postulated to regulate brain amyloid β (Aβ) levels by increased clearance via the choroid plexus. Growth factors, specifically fibroblast growth factor and IGF-1 receptors and/or their downstream signaling pathways may interact with the Klotho gene which functions as an aging suppressor gene. Neurons may not be the only cells affected by exercise. Glia (astrocytes and microglia), neurovascular units and the Fourth Element may also be affected in a differential fashion by the AD process. Analyses of these factors, as suggested by the multi-dimensional matrix approach, are needed to improve our understanding of this complex multi-factorial process, which is increasingly relevant to conquering the escalating and intersecting world-wide epidemics of dementia, diabetes, and sarcopenia that threaten the global healthcare system. Physical activity and interventions aimed at enhancing and/or mimicking the effects of exercise are likely to play a significant role in mitigating these epidemics, together with the embryonic efforts to develop cognitive rehabilitation for neurodegenerative disorders.

Keywords: entorhinal cortex; exponentially decreasing risk of cell death; hippocampus; insulin-like growth factor; loss of cognitive performance; p38 effector of Aβ-induced neurodegeneration; reduction of systemic inflammation; virtual reality environment.

Figure 1

Klotho protein and neuronal differentiation ratio of human neural stem cells (hNSC): NF–M (medium neurofilament protein) vs. astrocyte/GFAP (glial fibrillary acidic protein). (A) no treatment, (B) in the presence of rotenone; apoptosis with destruction of cell membrane and nucleus, loss of neuronal differentiation; (C) the addition of Klotho protein to rotenone increases survival, induces stem cell proliferation and neuronal differentiation (Rosenblatt and Foster, unpublished data).

Figure 2

Curve describing the kinetics of neuronal death in neurodegenerative diseases based on an animal model (adapted; Clarke et al., 2000). There is an exponential decline of neuronal number in time.

Figure 3

The exercise may halt the neurodegenerative process depending on the time of intervention.

Figure 4

Time course of the impairment continuum of cognition (adapted; Small et al., 2008).

Figure 5

Exercise, growth factors, myokines, Klotho, and potential effects on the brain.