Exercise-Induced Cognitive Improvement Is Associated with Sodium Channel-Mediated Excitability in APP/PS1 Mice

Abstract

Elevated brain activation, or hyperexcitability, induces cognitive impairment and confers an increased risk of Alzheimer's disease (AD). Blocking the overexcitation of the neural network may be a promising new strategy to prevent, halt, and even reverse this condition. Physical exercise has been shown to be an effective cognitive enhancer that reduces the risk of AD in elderly individuals, but the underlying mechanisms are far from being fully understood. We explored whether long-term treadmill exercise attenuates amyloid precursor protein (APP)/presenilin-1 (PS1) mutation-induced aberrant network activity and thus improves cognition by altering the numbers and/or distribution of voltage-gated sodium channels (Nav) in transgenic mice. APP/PS1 mice aged 2, 3.5, 5, 6.5, 8, and 9 months underwent treadmill exercise with different durations or at different stages of AD. The alterations in memory, electroencephalogram (EEG) recordings, and expression levels and distributions of Nav functional members (Nav1.1α, Nav1.2, Nav1.6, and Navβ2) were evaluated. The results revealed that treadmill exercise with 12and 24-week durations 1) induced significant improvement in novel object recognition (NOR) memory and Morris water maze (MWM) spatial memory; 2) partially reduced abnormal spike activity; and 3) redressed the disturbed cellular distribution of Nav1.1α, aberrant Navβ2 cleavage augmentation, and Nav1.6 upregulation. Additionally, APP/PS1 mice in the 24-week exercise group showed better performance in the NOR task and a large decrease in Nav1.6 expression, which was close to the wild-type level. This study suggests that exercise improves cognition and neural activity by altering the numbers and distribution of hippocampal Nav in APP/PS1 mice. Long-term treadmill exercise, for about 24 weeks, starting in the preclinical stage, is a promising therapeutic strategy for preventing AD and halting its progress.

Protection Induced By Ginsenoside Rb1 in Alzheimer’s Disease Model is Associated With Redressing The Neuronal Hyperexcitability Which is Regulated By Nav1.2 and Nav1.6

“…The abnormal expression and distribution of Nav1.6 was reported to be associated with various neurological disorders that characterized by neuronal hyperexcitability [21]. Moreover, we found that exercise training improved cognitive de cient of APP/PS1 mice mainly by altering the expression and distribution of Nav1.1α, Nav1.2 and Nav1.6 [22]. Therefore, to maintain the normal expressions and functions of Nav1.1α, Nav1.2 and Nav1.6 may be the key target for various treatments induced-improvement in cognitive and memory of AD.…”

“…Meanwhile, PNS is a medicine made of two or more ingredients, of which ginsenoside Rb1(Rb1) is a major component [6]. Rb1 has been shown to enhance the neuroprotective effect of neurons by upregulating brain-derived neurotrophic factor (BDNF) [7,8].…”

Axon Initial Segment Pathology in Alzheimer's Disease Mouse Model Disturbs the Action Potential Initiation and Propagation

“…Even the treatment of exogenous soluble Aβ 1-42 , which is the main secreted marker in the brain of AD patients, could also increase the Na v1.6 channel expression level. Previous studies showed increased excitability in mature cultured APP/PS1 neurons with the increased expression levels of sodium channels, especially the AISlocalized Na v1.6 channel [52,54,62,63]. These neurons were reported with a higher AP ring frequency and a lower threshold upon injecting a strong depolarizing current (i.e., 200 pA, 500 ms).…”

“…Axonal pathology in APP/PS1 neurons, accompanied by membrane proteins and ion channel alterations, could seriously affect intrinsic neuronal excitability [52][53][54][55]. In the present study, we found that wild-type neuron and APP/PS1 neurons have normal resting potential (WT: -69.1 ± 0.98 mV, n = 77; APP/PS1: -67.1 ± 0.82 mV, n = 48, ns P value = 0.1703) (Fig.…”

Reduced Expression of Voltage-Gated Sodium Channel Beta 2 Restores Neuronal Injury and Improves Cognitive Dysfunction Induced by Aβ1-42

“…Furthermore, Nav β 2-kd induces restoration of sodium current density and neuronal activity in hippocampal neurons, cognitive improvement in APP/PS1 transgenic mice, and promotion of the transformation of APP amyloid metabolic pathway to nonamyloid production process [ 26 ]. Studies have also revealed that cognitive protection induced by either exercise training or notoginsenoside R1 is associated with the regulation of Nav β 2 in the hippocampus of APP/PS1 mice [ 27 , 28 ]. Therefore, the evidence has proved that Nav β 2 plays crucial roles in cognitive dysfunction induced by brain aging and associated disorders, such as AD.…”