Synaptic Plasticity in the Hippocampus of a APP/PS1 Mouse Model of Alzheimer's Disease Is Impaired in Old but Not Young Mice

Gengler, Simon; Hamilton, Alison B.; Hölscher, Christian

doi:10.1371/journal.pone.0009764

Cited by 141 publications

(119 citation statements)

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“…In our study, first, we demonstrated that excess formaldehyde suppresses hippocampal LTP and spatial memory formation in rats (Figs. 2 and 4), consistent with other reports of hippocampal LTP suppression and memory decline in aged mice and rats (Almaguer et al 2002;Chapman et al 1999;Kamal et al 2005), STZ-induced diabetic SD rats (Reisi et al 2010), and Alzheimer's disease animal models such as APP transgenic mice (Gureviciene et al 2004), APP/ PS1 mice (Gengler et al 2010), and SAMP8 (López-Ramos et al 2012). Second, we showed that excess formaldehyde non-specifically blocks the NR1/NR2B subunits of the NMDA receptor in vitro (Fig.…”

Section: Discussionsupporting

confidence: 90%

“…Abundant evidence shows that memory decline occurs and hippocampal long-term potentiation (LTP) is impaired in aged animals (Almaguer et al 2002;Chapman et al 1999;Kamal et al 2005) and memory-deteriorating animal models such as amyloid precursor protein (APP) transgenic mice (Gureviciene et al 2004), APP/PS1 mice (Gengler et al 2010), and senescence-acceleratedprone 8 mice (SAMP8) (López-Ramos et al 2012). NR2B, one of the subunits of N-methyl-D-aspartate (NMDA) receptor, is critical in regulating the agedependent synaptic plasticity and memory formation (Tang et al 1999).…”

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confidence: 99%

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Accumulated hippocampal formaldehyde induces age-dependent memory decline

Tong

Han

Luo

et al. 2012

AGE

170

147

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Aging is an important factor in memory decline in aged animals and humans and in Alzheimer's disease and is associated with the impairment of hippocampal long-term potentiation (LTP) and downregulation of NR1/NR2B expression. Gaseous formaldehyde exposure is known to induce animal memory loss and human cognitive decline; however, it is unclear whether the concentrations of endogenous formaldehyde are elevated in the hippocampus and how excess formaldehyde affects LTP and memory formation during the aging process. In the present study, we report that hippocampal formaldehyde accumulated in memorydeteriorating diseases such as age-related dementia. Spatial memory performance was gradually impaired in normal Sprague-Dawley rats by persistent intraperitoneal injection with formaldehyde. Furthermore, excess formaldehyde treatment suppressed the hippocampal LTP formation by blocking N-methyl-D-aspartate (NMDA) receptor. Chronic excess formaldehyde treatment over a period of 30 days markedly decreased the viability of the hippocampus and down-regulated the expression of the NR1 and NR2B subunits of the NMDA receptor. Our results indicate that excess endogenous formaldehyde is a critical factor in memory loss in age-related memory-deteriorating diseases.

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Section: Discussionsupporting

confidence: 90%

mentioning

confidence: 99%

Accumulated hippocampal formaldehyde induces age-dependent memory decline

Tong

Han

Luo

et al. 2012

AGE

170

147

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“…Spatial learning deficits in the Morris water-maze, Y-maze, and contextual fear task had been reported in APPPS1 mice. 12,15 These deficits were detected in 8-month-old but not in younger APPPS1 mice. The episodic memory impairment is a cardinal symptom of AD and precedes a more global cognitive impairment.…”

Section: Discussionmentioning

confidence: 95%

Hypertension Accelerates the Progression of Alzheimer-Like Pathology in a Mouse Model of the Disease

et al. 2015

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A lzheimer disease (AD) accounts for 60% to 80% of dementia cases and represents the most common cause of dementia among the elderly.1 AD is a chronic neurodegenerative disorder characterized by the development of cortical extracellular amyloid plaques, mainly consisting of amyloid β peptide (Aβ) and the intracellular neurofibrillary tangles formed by the aggregated tau protein.2 Aβ is a proteolytic cleavage product of amyloid precursor protein (APP), ubiquitously expressed in the body. APP is processed sequentially by γ-and β-secretases to generate a heterogeneous group of peptides among which Aβ42 and Aβ40 are believed to be particularly important in the pathogenesis of AD.3 Although Aβ remains in the focus of AD research, the pathogenesis of AD is largely undefined and effective treatments are still not available. 4 The interest in the role of vascular factors in pathogenesis of neurodegenerative dementias has grown steadily during the past decade. It is now well recognized that cerebrovascular dysfunction could be an essential factor in the pathogenesis of many types of dementia and significantly affects both incidence and course of the disease. 5Cerebrovascular impairment, including cerebral amyloid angiopathy, brain-blood barrier impairment, and small vessel disease, is frequently observed in patients with AD and could influence clinical manifestation and severity of AD and contribute to cognitive decline. 6 In addition, cardiovascular risk factors have been associated with higher risk of developing AD.7,8 Cardiovascular disease preventing strategies, like antihypertensive medications, were correlated with better mental health outcomes later in Abstract-Cerebrovascular impairment is frequent in patients with Alzheimer disease and is believed to influence clinical manifestation and severity of the disease. Cardiovascular risk factors, especially hypertension, have been associated with higher risk of developing Alzheimer disease. To investigate the mechanisms underlying the hypertension, Alzheimer disease cross talk, we established a mouse model of dual pathology by infusing hypertensive doses of angiotensin II into transgenic APPPS1 mice overexpressing mutated human amyloid precursor and presenilin 1 proteins. At 4.5 months, at the early stage of disease progression, only hypertensive APPPS1 mice presented impairment of temporal order memory performance in the episodic-like memory task. This cognitive deficit was associated with an increased number of cortical amyloid deposits (223±5 versus 207±5 plaques/mm 2 ; P<0.05) and a 2-fold increase in soluble amyloid levels in the brain and in plasma. Hypertensive APPPS1 mice presented several cerebrovascular alterations, including a 25% reduction in cerebral microvessel density and a 30% to 40% increase in cerebral vascular amyloid deposits, as well as a decrease in vascular endothelial growth factor A expression in the brain, compared with normotensive APPPS1 mice. Moreover, the brain levels of nitric oxide synthase 1 and 3 and the nitrite/nitrate levels were...

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“…Several studies have shown that the GLP-1 and GLP-1 analogs such as Val(8)GLP-1 cross the BBB (Kastin et al, 2002;Gengler et al, 2010b). Peripheral injection of GLP-1 analogs intraperitoneally increased neuronal progenitor proliferation in the brain (During et al, 2003) and enhanced LTP and paired-pulse facilitation (PPF) in the hippocampus (Gengler et al, 2010a). These results suggest that treatment with GLP-1 analogs beneficially affects a number of the therapeutic targets associated with AD, such as impaired cognitive performance, reduced neuronal communication, neurodegenerative processes, and reduced neuronal regeneration (Hölscher and Li, 2010).…”

Section: Introductionmentioning

confidence: 99%

The Diabetes Drug Liraglutide Prevents Degenerative Processes in a Mouse Model of Alzheimer's Disease

McClean¹,

Parthsarathy²,

Faivre³

et al. 2011

J. Neurosci.

562

465

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Type 2 diabetes is a risk factor for Alzheimer's disease, most likely linked to an impairment of insulin signaling in the brain. The incretin hormone glucagon-like peptide-1 (GLP-1) facilitates insulin signaling, and novel long-lasting GLP-1 analogs, such as liraglutide, are on the market as diabetes therapeutics. GLP-1 has been shown to have neuroprotective properties in vitro and in vivo. Here we tested the effects of peripherally injected liraglutide in an Alzheimer mouse model, APP swe /PS1 ⌬E9 (APP/PS1). Liraglutide was shown to cross the blood-brain barrier in an acute study. Liraglutide was injected for 8 weeks at 25 nmol/kg body weight i.p. once daily in 7-month-old APP/PS1 and wild-type littermate controls. In APP/PS1 mice, liraglutide prevented memory impairments in object recognition and water maze tasks, and prevented synapse loss and deterioration of synaptic plasticity in the hippocampus, commonly observed in this model. Overall ␤-amyloid plaque count in the cortex and dense-core plaque numbers were reduced by 40 -50%, while levels of soluble amyloid oligomers were reduced by 25%. The inflammation response as measured by activated microglia numbers was halved in liraglutidetreated APP/PS1 mice. Numbers of young neurons in the dentate gyrus were increased in APP/PS1 mice with treatment. Liraglutide treatment had little effect on littermate control mice, whose behavior was comparable to wild-type saline controls; however, synaptic plasticity was enhanced in the drug group. Our results show that liraglutide prevents key neurodegenerative developments found in Alzheimer's disease, suggesting that GLP-1 analogs represent a novel treatment strategy for Alzheimer's disease.

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Synaptic Plasticity in the Hippocampus of a APP/PS1 Mouse Model of Alzheimer's Disease Is Impaired in Old but Not Young Mice

Cited by 141 publications

References 30 publications

Accumulated hippocampal formaldehyde induces age-dependent memory decline

Accumulated hippocampal formaldehyde induces age-dependent memory decline

Hypertension Accelerates the Progression of Alzheimer-Like Pathology in a Mouse Model of the Disease

The Diabetes Drug Liraglutide Prevents Degenerative Processes in a Mouse Model of Alzheimer's Disease

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