Age-related cognitive deficits, impaired long-term potentiation and reduction in synaptic marker density in mice lacking the β-amyloid precursor protein

Dawson, G. R.; Seabrook, Guy R.; Zheng, Hui; Smith, David W.; Graham, Simon J.; O'Dowd, GM; Bowery, B.J.; Boyce, Susan; Trumbauer, Myrna E.; Chen, H.Y; Ploeg, Lex H.T. Van der; Sirinathsinghji, D.J.S.

doi:10.1016/s0306-4522(98)00410-2

Cited by 313 publications

(248 citation statements)

References 42 publications

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“…Since cPLA 2 modifies the transport of several proteins between Golgi vesicles and plasma membranes in nonneuronal cells as we discussed above (Choukroun et al, 2000;Regan-Klapisz et al, 2009), cPLA 2 might regulate APP trafficking and metabolism similar to other synaptic proteins into various lipid compartments. Besides its role in A␤ peptide generation, APP protein is required for synaptic plasticity and other neuronal functions (Dawson et al, 1999;Priller et al, 2006). Moreover A␤ oligomers bind to the cognate A␤ extracellular domain of APP and generate a G protein-dependent intracellular signaling pathway through APP dimerization (Shaked et al, 2006(Shaked et al, , 2009.…”

Section: Discussionmentioning

confidence: 99%

Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit

Desbène

Malaplate-Armand

Youssef

et al. 2012

Neurobiology of Aging

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Soluble beta-amyloid (A␤) oligomers are considered to putatively play a critical role in the early synapse loss and cognitive impairment observed in Alzheimer's disease. We previously demonstrated that A␤ oligomers activate cytosolic phospholipase A 2 (cPLA 2 ), which specifically releases arachidonic acid from membrane phospholipids. We here observed that cPLA 2 gene inactivation prevented the alterations of cognitive abilities and the reduction of hippocampal synaptic markers levels noticed upon a single intracerebroventricular injection of A␤ oligomers in wild type mice. We further demonstrated that the A␤ oligomer-induced sphingomyelinase activation was suppressed and that phosphorylation of Akt/protein kinase B (PKB) was preserved in neuronal cells isolated from cPLA 2 Ϫ/Ϫ mice. Interestingly, expression of the A␤ precursor protein (APP) was reduced in hippocampus homogenates and neuronal cells from cPLA 2 Ϫ/Ϫ mice, but the relationship with the resistance of these mice to the A␤ oligomer toxicity requires further investigation. These results therefore show that cPLA 2 plays a key role in the A␤ oligomer-associated neurodegeneration, and as such represents a potential therapeutic target for the treatment of Alzheimer's disease.

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Section: Discussionmentioning

confidence: 99%

Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit

Desbène

Malaplate-Armand

Youssef

et al. 2012

Neurobiology of Aging

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“…Behavioral studies revealed that APP KO mice have decreased locomotor activity, reduced forelimb grip strength and deficits in the Morris water maze task as well as passive avoidance learning [41][42][43]. Electrophysiology studies show that these mice are also defective in long-term potentiation (LTP), which is associated with attenuated paired-pulse depression of GABA-mediated inhibitory postsynaptic currents [44].…”

Section: App Aplp1 and Aplp2 Single Ko Micementioning

confidence: 99%

APP physiological and pathophysiological functions: insights from animal models

Guo

Wang

et al. 2011

Cell Res

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The amyloid precursor protein (APP) has been under intensive study in recent years, mainly due to its critical role in the pathogenesis of Alzheimer's disease (AD). β-Amyloid (Aβ) peptides generated from APP proteolytic cleavage can aggregate, leading to plaque formation in human AD brains. Point mutations of APP affecting Aβ production are found to be causal for hereditary early onset familial AD. It is very likely that elucidating the physiological properties of APP will greatly facilitate the understanding of its role in AD pathogenesis. A number of APP loss-and gainof-function models have been established in model organisms including Caenorhabditis elegans, Drosophila, zebrafish and mouse. These in vivo models provide us valuable insights into APP physiological functions. In addition, several knock-in mouse models expressing mutant APP at a physiological level are available to allow us to study AD pathogenesis without APP overexpression. This article will review the current physiological and pathophysiological animal models of APP.

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“…These single null animals are viable and fertile, although aged mice deficient in APP show impairment in behavior and long-term potentiation (Zheng et al, 1995;Dawson et al, 1999;Phinney, 1999;Seabrook et al, 1999). The subtle phenotypes observed in each of the single null animals could be attributed in part to genetic redundancies, because mice doubly deficient in APP and APLP2 or APLP1 and APLP2 exhibit early postnatal lethality (von Koch et al, 1997;Heber et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Defective Neuromuscular Synapses in Mice Lacking Amyloid Precursor Protein (APP) and APP-Like Protein 2

et al. 2005

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Age-related cognitive deficits, impaired long-term potentiation and reduction in synaptic marker density in mice lacking the β-amyloid precursor protein

Cited by 313 publications

References 42 publications

Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit

Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit

APP physiological and pathophysiological functions: insights from animal models

Defective Neuromuscular Synapses in Mice Lacking Amyloid Precursor Protein (APP) and APP-Like Protein 2

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