Exercise Prevents Amyloid-β-Induced Hippocampal Network Disruption by Inhibiting GSK3β Activation

Abstract

Exercise is becoming a promising therapeutic approach to prevent alterations both in Alzheimer's disease (AD) patients and in transgenic models of AD. This neuroprotection has been associated with changes in hippocampal structure and function, as well as with the reduction of amyloid-β (Aβ) production and accumulation. However, whether exercise produces lasting changes in hippocampal population activity and renders it resistant to Aβ-induced network dysfunction is still unknown. Thus, we tested whether voluntary exercise changes hippocampal population activity and prevents its alteration in the presence of Aβ, which has been associated to glycogen synthase kinase-3β (GSK3β) activation. We found that the hippocampal population activity recorded in slices obtained from mice that exercised voluntarily (with free access to a running wheel for 21 days) exhibits higher power and faster frequency composition than slices obtained from sedentary animals. Moreover, the hippocampal network of mice that exercised becomes insensitive to Aβ-induced inhibition of spontaneous population activity. This protective effect correlates with the inability of Aβ to activate GSK3β, is mimicked by GSK3β inhibition with SB126763 (in slices obtained from sedentary mice), and is abolished by the inhibition of PI3K with LY294002 (in slices obtained from mice that exercised). We conclude that voluntary exercise produces a lasting protective state in the hippocampus, maintained in hippocampal slices by a PI3K-dependent mechanism that precludes its functional disruption in the presence of Aβ by avoiding GSK3β activation.

Amyloid β Peptide-Induced Changes in Prefrontal Cortex Activity and Its Response to Hippocampal Input

“…As was already mentioned, alterations in PFC-controlled behaviors [18–20] and function [18–20] can be induced by intrahippocampal injection of A β . It is well known that A β affects hippocampal function both in vivo [37, 50] and in vitro [33, 45, 51] and, here, we show that A β can affect hippocampal input into the PFC. As this connection is required for the proper synchronization between these two structures and for normal PFC function [18, 19, 26, 27, 32], it is likely that PFC-hippocampal uncoupling could contribute to A β -induced pathology and, perhaps, to AD.…”

“…The oligomerization procedure was performed as previously described [33, 34]. Briefly, solid A β 1-42 peptide was dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) to a final concentration of 1 mM.…”

Aerobic Exercise Regulates Apoptosis through the PI3K/Akt/GSK-3β Signaling Pathway to Improve Cognitive Impairment in Alzheimer’s Disease Mice

“…Eight weeks of running table exercise increased the number and level of PI3K- and p-Akt positive cells and decreased GSK-3 β -positive neuronal number and protein expression. Exercise exerts neuroprotective effects via the PI3K/Akt pathway [ 38 ] and suppresses GSK3 β expression while improving hippocampal morphology and learning memory in mice with AD [ 39 ], which may explain the protection of neurons in AD mice by AE through the PI3K/Akt/GSK3- β pathway.…”

Changes in 24 h Rhythmicity of Spontaneous Locomotor Activity in the Triple Transgenic Mouse for Alzheimer’s Disease (3xTg-AD) in a Jet Lag Protocol: Correlations with Retinal Sensitivity

“…The differences with the study by Sterniczuk et al [ 20 ] are possibly due to the use of a wheel and their choice of putting together a pool of mice before and after the establishment of histopathological markers. However, we believe that an environment without a running wheel allows researchers to observe spontaneous motor activity without the motivational influence of the wheel and reduces the effect of physical exercise that delays the development of AD by increasing neuronal and vascular plasticity in areas affected by AD [ 39 40 ].…”