Treadmill Exercise Prevents Decline in Spatial Learning and Memory in 3×Tg-AD Mice through Enhancement of Structural Synaptic Plasticity of the Hippocampus and Prefrontal Cortex

Mu, Lianwei; Cai, Jiajia; Gu, Boya; Yu, Laikang; Cui, Li; Liu, Qing-song; Zhao, Li

doi:10.3390/cells11020244

Cited by 44 publications

(40 citation statements)

References 82 publications

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“…Nowadays, physical activity and exercise have been widely acknowledged as effective strategies for improving AD pathology and AD-associated cognitive impairment ( Northey et al, 2018 ; Jia et al, 2019 ; de Farias et al, 2021 ). From a mechanistic perspective, macroscopically, regular exercise has been shown to alleviate some abnormalities of brain structure and function and to increase cerebral blood flow in subjects with mild cognitive impairment (MCI) and AD ( Broadhouse et al, 2020 ; Tomoto et al, 2021 ; Yu et al, 2021 ); microscopically, exercise training not only increases levels of exerkines (e.g., irisin, Lourenco et al, 2019 ; Islam et al, 2021 ) and metabolic factors (e.g., lactate, El Hayek et al, 2019 ) in the peripheral circulation, which act on the AD brain indirectly, but also exert direct neuroprotective effects by increasing levels of brain-derived neurotrophic factor (BDNF) ( Wang and Holsinger, 2018 ) and promoting adult hippocampal neurogenesis ( Choi et al, 2018 ), enhancing synaptic plasticity ( Mu et al, 2022 ), reducing neuroinflammation and oxidative stress ( Zhang et al, 2019 ), and ameliorating Aβ deposition and tau hyperphosphorylation ( Brown et al, 2019 ). Strikingly, the activity of central neurotransmitter systems seems to be strongly modulated by exercise.…”

Section: Introductionmentioning

confidence: 99%

Understanding How Physical Exercise Improves Alzheimer’s Disease: Cholinergic and Monoaminergic Systems

Zong

Zhang

et al. 2022

Front. Aging Neurosci.

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Alzheimer’s disease (AD) is an age-related neurodegenerative disorder, characterized by the accumulation of proteinaceous aggregates and neurofibrillary lesions composed of β-amyloid (Aβ) peptide and hyperphosphorylated microtubule-associated protein tau, respectively. It has long been known that dysregulation of cholinergic and monoaminergic (i.e., dopaminergic, serotoninergic, and noradrenergic) systems is involved in the pathogenesis of AD. Abnormalities in neuronal activity, neurotransmitter signaling input, and receptor function exaggerate Aβ deposition and tau hyperphosphorylation. Maintenance of normal neurotransmission is essential to halt AD progression. Most neurotransmitters and neurotransmitter-related drugs modulate the pathology of AD and improve cognitive function through G protein-coupled receptors (GPCRs). Exercise therapies provide an important alternative or adjunctive intervention for AD. Cumulative evidence indicates that exercise can prevent multiple pathological features found in AD and improve cognitive function through delaying the degeneration of cholinergic and monoaminergic neurons; increasing levels of acetylcholine, norepinephrine, serotonin, and dopamine; and modulating the activity of certain neurotransmitter-related GPCRs. Emerging insights into the mechanistic links among exercise, the neurotransmitter system, and AD highlight the potential of this intervention as a therapeutic approach for AD.

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Section: Introductionmentioning

confidence: 99%

Understanding How Physical Exercise Improves Alzheimer’s Disease: Cholinergic and Monoaminergic Systems

Zong

Zhang

et al. 2022

Front. Aging Neurosci.

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“…Numerous functions regulated by GS14 in the spines include the role of various G proteins and Ca2+/calmodulin signaling [ 76 ]. Another study has demonstrated the increased number and activity of spines, reduced in a mouse family affected by an Alzheimer’s disease model, reaches values of normal mice after months of treadmill exercise [ 77 ]. It appears, therefore, that brain functions, including learning and memory, can be protected at the level of spines by appropriate physical exercise.…”

Section: Post-synapses With Spinesmentioning

confidence: 99%

“…This section is not entirely distinct from the previous ones. Indeed, many studies about structure and function of post-synapses, especially those concerning the spines, include sections dealing with diseases; see for example [ 16 , 25 , 53 , 73 , 75 , 77 ]. The difference between the previously mentioned articles and those of this section deals not with different areas but with different approaches, the most important in the present section.…”

Section: Post-synapse Alterations In Brain Diseasesmentioning

confidence: 99%

“…Investigation of synapses, particularly of the spines, can therefore be very relevant to the understanding of the diseases and for the development of their therapy. Lesion examples have been anticipated in the previous section [ 32 , 77 , 82 ]. Here attention is focused on specific aspects of these diseases.…”

Section: Post-synapse Alterations In Brain Diseasesmentioning

confidence: 99%

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Post-Synapses in the Brain: Role of Dendritic and Spine Structures

Meldolesi

2022

Biomedicines

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Brain synapses are neuronal structures of the greatest interest. For a long time, however, the knowledge about them was variable, and interest was mostly focused on their pre-synaptic portions, especially neurotransmitter release from axon terminals. In the present review interest is focused on post-synapses, the structures receiving and converting pre-synaptic messages. Upon further modulation, such messages are transferred to dendritic fibers. Dendrites are profoundly different from axons; they are shorter and of variable thickness. Their post-synapses are of two types. Those called flat/intended/aspines, integrated into dendritic fibers, are very frequent in inhibitory neurons. The spines, small and stemming protrusions, connected to dendritic fibers by their necks, are present in almost all excitatory neurons. Several structures and functions including the post-synaptic densities and associated proteins, the nanoscale mechanisms of compartmentalization, the cytoskeletons of actin and microtubules, are analogous in the two post-synaptic forms. However other properties, such as plasticity and its functions of learning and memory, are largely distinct. Several properties of spines, including emersion from dendritic fibers, growth, change in shape and decreases in size up to disappearance, are specific. Spinal heads correspond to largely independent signaling compartments. They are motile, their local signaling is fast, however transport through their thin necks is slow. When single spines are activated separately, their dendritic effects are often lacking; when multiple spines are activated concomitantly, their effects take place. Defects of post-synaptic responses, especially those of spines, take place in various brain diseases. Here alterations affecting symptoms and future therapy are shown to occur in neurodegenerative diseases and autism spectrum disorders.

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“…We and others have shown that physical exercise decreases Aβ burden and alleviates synapse loss and impairment of learning and memory in mouse models [ 28 , 29 , 30 ]. Meanwhile, exercise reduces the activation of microglia and astrocytes and neuroinflammation and preserves cognitive function in 3 × Tg-AD mice [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

Treadmill Exercise Reduces Neuroinflammation, Glial Cell Activation and Improves Synaptic Transmission in the Prefrontal Cortex in 3 × Tg-AD Mice

Xia

Cai

et al. 2022

IJMS

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Physical exercise improves memory and cognition in physiological aging and Alzheimer’s disease (AD), but the mechanisms remain poorly understood. Here, we test the hypothesis that Aβ oligomer accumulation, neuroinflammation, and glial cell activation may lead to disruption of synaptic transmission in the prefrontal cortex of 3 × Tg-AD Mice, resulting in impairment of learning and memory. On the other hand, treadmill exercise could prevent the pathogenesis and exert neuroprotective effects. Here, we used immunohistochemistry, western blotting, enzyme-linked immunosorbent assay, and slice electrophysiology to analyze the levels of GSK3β, Aβ oligomers (Aβ dimers and trimers), pro-inflammatory cytokines (IL-1β, IL-6, and TNFα), the phosphorylation of CRMP2 at Thr514, and synaptic currents in pyramidal neurons in the prefrontal cortex. We show that 12-week treadmill exercise beginning in three-month-old mice led to the inhibition of GSK3β kinase activity, decreases in the levels of Aβ oligomers, pro-inflammatory cytokines (IL-1β, IL-6, and TNFα), and the phosphorylation of CRMP2 at Thr514, reduction of microglial and astrocyte activation, and improvement of excitatory and inhibitory synaptic transmission of pyramidal neurons in the prefrontal cortex of 3 × Tg-AD Mice. Thus, treadmill exercise reduces neuroinflammation, glial cell activation and improves synaptic transmission in the prefrontal cortex in 3 × Tg-AD mice, possibly related to the inhibition of GSK3β kinase activity.

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Treadmill Exercise Prevents Decline in Spatial Learning and Memory in 3×Tg-AD Mice through Enhancement of Structural Synaptic Plasticity of the Hippocampus and Prefrontal Cortex

Cited by 44 publications

References 82 publications

Understanding How Physical Exercise Improves Alzheimer’s Disease: Cholinergic and Monoaminergic Systems

Understanding How Physical Exercise Improves Alzheimer’s Disease: Cholinergic and Monoaminergic Systems

Post-Synapses in the Brain: Role of Dendritic and Spine Structures

Treadmill Exercise Reduces Neuroinflammation, Glial Cell Activation and Improves Synaptic Transmission in the Prefrontal Cortex in 3 × Tg-AD Mice

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