A Comparative Study Evaluating the Impact of Physical Exercise on Disease Progression in a Mouse Model of Alzheimer’s Disease

Maliszewska-Cyna, Ewelina; Xhima, Kristiana; Aubert, Isabelle

doi:10.3233/jad-150660

Cited by 34 publications

(20 citation statements)

References 66 publications

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“…Behavioral deficits in the Tg mice are robust, given that significant differences persisted despite being housed in cages with running wheels. Previous research has shown that wheel-running exercise in AD mice led to improved performance in various behavioral tasks, including: Barnes Maze (Walker et al, 2015 ), Y-maze (Maliszewska-Cyna et al, 2016 ), and the MWM (Adlard et al, 2005 ). In addition, voluntary wheel running has also been shown to decrease plaque pathology (Adlard et al, 2005 ).…”

Section: Discussionmentioning

confidence: 99%

A Novel hAPP/htau Mouse Model of Alzheimer's Disease: Inclusion of APP With Tau Exacerbates Behavioral Deficits and Zinc Administration Heightens Tangle Pathology

Lippi

Smith

Flinn

2018

Front. Aging Neurosci.

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The brains of those with Alzheimer's disease have amyloid and tau pathology; thus, mice modeling AD should have both markers. In this study, we characterize offspring from the cross of the J20 (hAPP) and rTg4510 (htau) strains (referred to as dual Tg). Behavior was assessed at both 3.5 and 7 months, and biochemical differences were assessed at 8 months. Additionally, mice were placed on zinc (Zn) water or standard lab water in order to determine the role of this essential biometal. Behavioral measures examined cognition, emotion, and aspects of daily living. Transgenic mice (dual Tg and htau) showed significant deficits in spatial memory in the Barnes Maze at both 3.5 and 7 months compared to controls. At 7 months, dual Tg mice performed significantly worse than htau mice (p < 0.01). Open field and elevated zero maze (EZM) data indicated that dual Tg and htau mice displayed behavioral disinhibition compared to control mice at both 3.5 and 7 months (p < 0.001). Transgenic mice showed significant deficits in activities of daily living, including burrowing and nesting, at both 3.5 and 7 months compared to control mice (p < 0.01). Dual Tg mice built very poor nests, indicating that non-cognitive tasks are also impacted by AD. Overall, dual Tg mice demonstrated behavioral deficits earlier than those shown by the htau mice. In the brain, dual Tg mice had significantly less free Zn compared to control mice in both the dentate gyrus and the CA3 of the hippocampus (p < 0.01). Dual Tg mice had increased tangles and plaques in the hippocampus compared to htau mice and the dual Tg mice given Zn water displayed increased tangle pathology in the hippocampus compared to htau mice on Zn water (p < 0.05). The dual Tg mouse described here displays pathology reminiscent of the human AD condition and is impaired early on in both cognitive and non-cognitive behaviors. This new mouse model allows researchers to assess how both amyloid and tau in combination impact behavior and brain pathology.

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Section: Discussionmentioning

confidence: 99%

A Novel hAPP/htau Mouse Model of Alzheimer's Disease: Inclusion of APP With Tau Exacerbates Behavioral Deficits and Zinc Administration Heightens Tangle Pathology

Lippi

Smith

Flinn

2018

Front. Aging Neurosci.

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“…Substantial evidence suggests that increased physical activity or an active lifestyle beneficially affects human brain health (Scarmeas et al, 2009), and reduces the pathological plaque load and improves cognition in patients with AD (Maliszewska-Cyna et al, 2016). However, the mechanisms underlying the effect of physical activity on the reduction of plaque remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Voluntary Exercise Promotes Glymphatic Clearance of Amyloid Beta and Reduces the Activation of Astrocytes and Microglia in Aged Mice

Liu

Zhang

et al. 2017

Front. Mol. Neurosci.

253

192

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Age is characterized by chronic inflammation, leading to synaptic dysfunction and dementia because the clearance of protein waste is reduced. The clearance of proteins depends partly on the permeation of the blood–brain barrier (BBB) or on the exchange of water and soluble contents between the cerebrospinal fluid (CSF) and the interstitial fluid (ISF). A wealth of evidence indicates that physical exercise improves memory and cognition in neurodegenerative diseases during aging, such as Alzheimer’s disease (AD), but the influence of physical training on glymphatic clearance, BBB permeability and neuroinflammation remains unclear. In this study, glymphatic clearance and BBB permeability were evaluated in aged mice using in vivo two-photon imaging. The mice performed voluntary wheel running exercise and their water-maze cognition was assessed; the expression of the astrocytic water channel aquaporin 4 (AQP4), astrocyte and microglial activation, and the accumulation of amyloid beta (Aβ) were evaluated with immunofluorescence or an enzyme-linked immunosorbent assay (ELISA); synaptic function was investigated with Thy1–green fluorescent protein (GFP) transgenic mice and immunofluorescent staining. Voluntary wheel running significantly improved water-maze cognition in the aged mice, accelerated the efficiency of glymphatic clearance, but which did not affect BBB permeability. The numbers of activated astrocytes and microglia decreased, AQP4 expression increased, and the distribution of astrocytic AQP4 was rearranged. Aβ accumulation decreased, whereas dendrites, dendritic spines and postsynaptic density protein (PSD95) increased. Our study suggests that voluntary wheel running accelerated glymphatic clearance but not BBB permeation, improved astrocytic AQP4 expression and polarization, attenuated the accumulation of amyloid plaques and neuroinflammation, and ultimately protected mice against synaptic dysfunction and a decline in spatial cognition. These data suggest possible mechanisms for exercise-induced neuroprotection in the aging brain.

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“…Running has also been shown to reduce microglia activation and cytokine levels in the hippocampus of aged mice, representing another mechanism by which exercise may protect the neurovascular unit and in turn, the brain from insult [ 6, 94, 95 ]. In models of advanced aging and Alzheimer’s disease (AD), exercise reduces soluble amyloid-beta (A β ) load and plaque formation, in part mediated by glymphatic clearance and proteolytic degradation [ 76, 94, 96–99 ]. Voluntary exercise has also been shown to delay white matter atrophy and protect cerebral vasculature in mouse models of AD, correlating with improved performance on spatial memory tasks [ 100–102 ].…”

Section: Introductionmentioning

confidence: 99%

The Neuroprotective Effects of Exercise: Maintaining a Healthy Brain Throughout Aging

Vecchio

Meng

Xhima

et al. 2018

BPL

Self Cite

152

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Physical activity plays an essential role in maintaining a healthy body, yet it also provides unique benefits for the vascular and cellular systems that sustain a healthy brain. While the benefit of exercise has been observed in humans of all ages, the availability of preclinical models has permitted systematic investigations into the mechanisms by which exercise supports and protects the brain. Over the past twenty-five years, rodent models have shown that increased physical activity elevates neurotrophic factors in the hippocampal and cortical areas, facilitating neurotransmission throughout the brain. Increased physical activity (such as by the voluntary use of a running wheel or regular, timed sessions on a treadmill) also promotes proliferation, maturation and survival of cells in the dentate gyrus, contributing to the process of adult hippocampal neurogenesis. In this way, rodent studies have tremendous value as they demonstrate that an ‘active lifestyle’ has the capacity to ameliorate a number of age–related changes in the brain, including the decline in adult neurogenesis. Moreover, these studies have shown that greater physical activity may protect the brain health into advanced age through a number of complimentary mechanisms: in addition to upregulating factors in pro-survival neurotrophic pathways and enhancing synaptic plasticity, increased physical activity promotes brain health by supporting the cerebrovasculature, sustaining the integrity of the blood–brain barrier, increasing glymphatic clearance and proteolytic degradation of amyloid beta species, and regulating microglia activation. Collectively, preclinical studies demonstrate that exercise initiates diverse and powerful neuroprotective pathways that may converge to promote continued brain health into old age. This review will draw on both seminal and current literature that highlights mechanisms by which exercise supports the functioning of the brain, and aids in its protection.

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A Comparative Study Evaluating the Impact of Physical Exercise on Disease Progression in a Mouse Model of Alzheimer’s Disease

Cited by 34 publications

References 66 publications

A Novel hAPP/htau Mouse Model of Alzheimer's Disease: Inclusion of APP With Tau Exacerbates Behavioral Deficits and Zinc Administration Heightens Tangle Pathology

A Novel hAPP/htau Mouse Model of Alzheimer's Disease: Inclusion of APP With Tau Exacerbates Behavioral Deficits and Zinc Administration Heightens Tangle Pathology

Voluntary Exercise Promotes Glymphatic Clearance of Amyloid Beta and Reduces the Activation of Astrocytes and Microglia in Aged Mice

The Neuroprotective Effects of Exercise: Maintaining a Healthy Brain Throughout Aging

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