Age- and Brain Region-Specific Changes of Glucose Metabolic Disorder, Learning, and Memory Dysfunction in Early Alzheimer’s Disease Assessed in APP/PS1 Transgenic Mice Using 18F-FDG-PET

Li, Xueyuan; Men, Weiwei; Zhu, Hua; Lei, Jianfeng; Zuo, Fuxing; Wang, Zhan-Jing; Zhu, Z.H.; Bao, Xinjie; Wang, Renzhi

doi:10.3390/ijms17101707

Cited by 62 publications

(54 citation statements)

References 40 publications

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“…Our earlier studies reported that those mice exhibited notable learning and memory deficits at 8 months of age (Li X.-F. et al, 2016). In this study, we further showed that PBS-treated AD mice exhibited notable disorders in the anxiety and recognition compared with WT mice.…”

Section: Discussionmentioning

confidence: 94%

Human Neural Stem Cell Transplantation Rescues Cognitive Defects in APP/PS1 Model of Alzheimer’s Disease by Enhancing Neuronal Connectivity and Metabolic Activity

Zhu

Sun

et al. 2016

Front. Aging Neurosci.

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Alzheimer’s disease (AD), the most frequent type of dementia, is featured by Aβ pathology, neural degeneration and cognitive decline. To date, there is no cure for this disease. Neural stem cell (NSC) transplantation provides new promise for treating AD. Many studies report that intra-hippocampal transplantation of murine NSCs improved cognition in rodents with AD by alleviating neurodegeneration via neuronal complement or replacement. However, few reports examined the potential of human NSC transplantation for AD. In this study, we implanted human brain-derived NSCs (hNSCs) into bilateral hippocampus of an amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic (Tg) mouse model of AD to test the effects of hNSC transplantation on Alzheimer’s behavior and neuropathology. Six weeks later, transplanted hNSCs engrafted into the brains of AD mice, migrated dispersedly in broad brain regions, and some of them differentiated into neural cell types of central nervous system (CNS). The hNSC transplantation restored the recognition, learning and memory deficits but not anxiety tasks in AD mice. Although Aβ plaques were not significantly reduced, the neuronal, synaptic and nerve fiber density was significantly increased in the frontal cortex and hippocampus of hNSC-treated AD mice, suggesting of improved neuronal connectivity in AD brains after hNSC transplantation. Ultrastructural analysis confirmed that synapses and nerve fibers maintained relatively well-structured shapes in these mice. Furthermore, in vivo magnetic resonance spectroscopy (MRS) showed that hNSC-treated mice had notably increased levels of N-acetylaspartate (NAA) and Glu in the frontal cortex and hippocampus, suggesting that neuronal metabolic activity was improved in AD brains after hNSC transplantation. These results suggest that transplanted hNSCs rescued Alzheimer’s cognition by enhancing neuronal connectivity and metabolic activity through a compensation mechanism in APP/PS1 mice. This study provides preclinical evidence that hNSC transplantation can be a possible and feasible strategy for treating patients with AD.

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Section: Discussionmentioning

confidence: 94%

Human Neural Stem Cell Transplantation Rescues Cognitive Defects in APP/PS1 Model of Alzheimer’s Disease by Enhancing Neuronal Connectivity and Metabolic Activity

Zhu

Sun

et al. 2016

Front. Aging Neurosci.

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“…The APP/PS1 transgenic mouse is the most commonly used AD model, which develops spatial memory impairment, increased Aβ deposition in the brain, synaptic loss, and neuronal loss similar to those features observed in AD [39,40]. It has been reported that the amyloid plaque can occur in the neocortex at 6-8 weeks and signi cantly increase at 8 months old [41], the synaptic dysfunction appears at about 3 months old [42], and the cognitive disability starts to show at about 6 months old in the APP/PS1 mice [43].…”

Section: Discussionmentioning

confidence: 99%

Ginsenoside Rg1 alleviates Aβ deposition and neuronal damage by inhibiting NLRP1 inflammasome activation in APP/PS1 mice

Zhang¹,

Su²,

Sun³

et al. 2020

Preprint

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Background: Oxidative stress and neuroinflammation play important roles in the whole pathogenesis of Alzheimer's disease (AD). NADPH oxidase 2 (NOX2) is an important enzyme that is responsible for ROS generation in many neurodegenerative diseases. The nucleotide-binding oligomerization domain (NOD)-like receptor protein 1 (NLRP1) inflammasome is responsible for the formation of pro-inflammatory molecules in neurons. However, it is still unclear whether inhibition of NOX2 and NLRP1 inflammasome decreases amyloid-beta (Aβ) generation and deposition in APP/PS1 mice. Ginsenoside Rg1 (Rg1) is an active component in ginseng, and maybe a potential agent for neurodegenerative diseases. In this study, we investigated the effects and mechanisms of Rg1 treatment on cognitive performance, neuronal damage, Aβ deposition and NOX2-NLRP1 inflammasome activation in APP/PS1 mice.Methods: WT and APP/PS1 mice were used in the experiment from 6 months (M) old to 9M old, and 6M APP/PS1 mice were used as pre-treatment controls. The open field test (OFT) and Morris water maze (MWM) were used to detect behavioral change and cognitive function. The H&E and Nissl staining were used to assess neuronal damage. We further examined PSD95 expression, Aβ generation and deposition, Tau and p-Tau expression, NOX2-mediated ROS generation and NLRP1 inflammasome activation by using immunofluorescence, western blot analysis, and real time q-PCR.Results: Rg1 treatment for 12 weeks alleviated learning and memory impairments and neuronal damage, decreased p-Tau level, APP expression and Aβ deposition in APP/PS1 mice. Meanwhile, Rg1 treatment significantly decreased the levels of ROS and IL-1β, and reduced the expressions of NOX2 and NLRP1 inflammasome in the brain cortex and hippocampus in APP/PS1 mice. Furthermore, apocynin (a NOX inhibitor) and NLRP1-siRNA treatment also alleviated cognitive impairments, neuronal damage and Aβ deposition, and reduced the expression of NLRP1 inflammasome in brain cortex and hippocampus in APP/PS1 mice.Conclusions: Rg1 treatment could alleviate learning and memory impairment, neuronal damage, and reduce Aβ generation and deposition by inhibiting NLRP1 inflammasome activation in APP/PS1 mice.

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“…The transgenes were confirmed by PCR genotyping of mouse tail tissue [31,32]. Only female mice were utilized because female APP/PS1 mice develop cognitive deficits faster than the male mice [33].…”

Section: Animalmentioning

confidence: 99%

“…Previous study used 18F-labeled fluorodeoxyglucose (FDG) microPET detecting the brains of APP/PS1 transgenic (TG) mice to evaluate age-and brain region-specific changes of glucose metabolism, which demonstrated that APP/PS1 mice showed intact cognition at age 2 months (m), learning deficits at 3.5 m, learning and memory deficits at 5 m, and further learning and memory impairments at 8 m [33]. It seems that APP/PS1 mice of 2 m mimic the preclinical stage of AD (prodromal-AD), whereas APP/PS1 mice of 3.5 m, 5 m, and 8 m exhibit subclinical, early clinical, and midclinical signs of AD (symptomatic-AD) [33]. As medium-/longterm exercise induces promising improvements in learning and memory [9,34], we studied the impact of medium-/long-term treadmill exercise (for 12 and 24 weeks, respectively) on mice at different stages of AD.…”

Section: Animalmentioning

confidence: 99%

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

et al. 2020

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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.

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Age- and Brain Region-Specific Changes of Glucose Metabolic Disorder, Learning, and Memory Dysfunction in Early Alzheimer’s Disease Assessed in APP/PS1 Transgenic Mice Using 18F-FDG-PET

Cited by 62 publications

References 40 publications

Human Neural Stem Cell Transplantation Rescues Cognitive Defects in APP/PS1 Model of Alzheimer’s Disease by Enhancing Neuronal Connectivity and Metabolic Activity

Human Neural Stem Cell Transplantation Rescues Cognitive Defects in APP/PS1 Model of Alzheimer’s Disease by Enhancing Neuronal Connectivity and Metabolic Activity

Ginsenoside Rg1 alleviates Aβ deposition and neuronal damage by inhibiting NLRP1 inflammasome activation in APP/PS1 mice

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

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