Endogenous secreted amyloid precursor protein-α regulates hippocampal NMDA receptor function, long-term potentiation and spatial memory

Taylor, C J; Ireland, David; Ballagh, Irene H.; Bourne, Katie; Marechal, Nicola M.; Turner, Paul; Bilkey, David K.; Tate, Warren P.; Abraham, Wickliffe C.

doi:10.1016/j.nbd.2008.04.011

Cited by 170 publications

(199 citation statements)

References 55 publications

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“…It was thus suggested that decreased amounts of sAPP␣ in AD brain contributed to the memory deficit characterizing AD, independently of A␤ toxicity. Consistent with these observations, analyses in rodents have shown a role for sAPP␣ in spatial memory (Bour et al, 2004;Ring et al, 2007;Taylor et al, 2008). Our data establish that in the fly a memory deficit is caused by loss of APPL function independently of the toxicity of the amyloid pathway, thus giving further support to the hypothesis that loss of function might contribute to early AD cognitive decline.…”

Section: Discussionsupporting

confidence: 87%

“…These studies have relied upon knock-out (KO) (Dawson et al, 1999;Phinney et al, 1999;Senechal et al, 2008) or knock-in techniques (Ring et al, 2007) or injection of anti-APP antibodies (Taylor et al, 2008) or antisense oligonucleotides (Senechal et al, 2007). Single APP KO leads to relatively mild behavioral defects, probably caused by functional redundancy (Muller et al, 1994;Zheng et al, 1995), while the adult APP Ϫ/Ϫ APLP1 Ϫ/Ϫ APLP2 Ϫ/Ϫ triple KO cannot be analyzed because of early postnatal lethality (Herms et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

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DrosophilaAmyloid Precursor Protein-Like Is Required for Long-Term Memory

Goguel¹,

Belair²,

Ayaz³

et al. 2011

J. Neurosci.

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The amyloid precursor protein (APP) plays an important role in Alzheimer's disease (AD), a progressive neurodegenerative pathology that first manifests as a decline of memory. While the main hypothesis for AD pathology centers on the proteolytic processing of APP, very little is known about the physiological function of the APP protein in the adult brain. Likewise, whether APP loss of function contributes to AD remains unclear. Drosophila has been used extensively as a model organism to study neuronal function and pathology. In addition, many of the molecular mechanisms underlying memory are thought to be conserved from flies to mammals, prompting us to study the function of APPL, the fly APP ortholog, during associative memory. It was previously shown that APPL expression is highly enriched in the mushroom bodies (MBs), a specialized brain structure involved in olfactory memory. We analyzed memory in flies in which APPL expression has been silenced specifically and transiently in the adult MBs. Our results show that in adult flies, APPL is not required for learning but is specifically involved in long-term memory, a long lasting memory whose formation requires de novo protein synthesis and is thought to require synaptic structural plasticity. These data support the hypothesis that disruption of normal APP function may contribute to early AD cognitive impairment.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

DrosophilaAmyloid Precursor Protein-Like Is Required for Long-Term Memory

Goguel¹,

Belair²,

Ayaz³

et al. 2011

J. Neurosci.

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“…Interestingly, all of the phenotypes reported in APP deficient mice including body and brain weight deficits, grip strength deficits, alterations in locomotor activity, and impaired spatial learning and LTP have been shown to be fully restored by expressing only APPsa (Ring et al 2007). Consistently, Taylor et al (2008) showed a requirement for APPsa for in vivo LTP employing infusion of a-secretase inhibitor or recombinant APPsa, respectively. This crucial function of APPsa for synaptic plasticity and cognition is also of relevance for AD, as reduced CSF levels of APPsa and a-secretase ADAM10 are prominent features of sporadic AD cases (Lannfelt et al 1995;Sennvik et al 2000;Colciaghi et al 2002;Tyler et al 2002).…”

Section: In Vivo Defined Genetic Modifications Of App Proteinsmentioning

confidence: 57%

“…Moderate overexpression of APP in transgenic mice, infusion of APPsa or the RERMS pentapeptide into the ventricle, or an indirect increase of APPsa levels because of overexpression of a-secretase, has been shown to increase synaptic density (Mucke et al 1994;Roch et al 1994;Meziane et al 1998;Bell et al 2008). Moreover, gain-or loss-of-function studies with either intraventricular APPsa infusion, down-regulation by antibody infusion or pharmacological inhibition of a-secretase coherently showed a function for APPsa in spatial memory and for LTP (Turner et al 2003;Taylor et al 2008). …”

Section: Neural and Synapto-trophic Functionsmentioning

confidence: 97%

Physiological Functions of APP Family Proteins

Müller¹,

Zheng²

2011

Cold Spring Harbor Perspectives in Medicine

270

235

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Biochemical and genetic evidence establishes a central role of the amyloid precursor protein (APP) in Alzheimer disease (AD) pathogenesis. Biochemically, deposition of the b-amyloid (Ab) peptides produced from proteolytic processing of APP forms the defining pathological hallmark of AD; genetically, both point mutations and duplications of wild-type APP are linked to a subset of early onset of familial AD (FAD) and cerebral amyloid angiopathy. As such, the biological functions of APP and its processing products have been the subject of intense investigation, and the past 20þ years of research have met with both excitement and challenges. This article will review the current understanding of the physiological functions of APP in the context of APP family members.

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“…In particular, there is currently no consensus whether APP/APLPs function primarily as cell surface receptor-like proteins mediating signaling and/or cell adhesion (Soba et al 2005;Anliker and Müller 2006), or whether APP functions are mediated by the secreted ectodomain APPs (Herms et al 2004;Ring et al 2007;Taylor et al 2008). In this regard, although APPsa has been implicated in many physiological processes, including neuroprotection, neurite outgrowth, the modulation of ion channels and synaptic plasticity, and neurogenesis (Mattson et al 1993;Furukawa et al 1996;Mattson and Furukawa 1998;Ring et al 2007;Taylor et al 2008;Perez et al 1997;Gakhar-Koppole et al 2008;Caille et al 2004), the cognate APPsa receptor(s) has not been identified so far. It was therefore met with excitement when a novel N-terminal fragment (N-APP 286 ) derived from APPsb was identified as a ligand for death receptor 6 (DR6), a member of the TNFR gene family (Nikolaev et al 2009).…”

Section: App Interactors and Signalingmentioning

confidence: 99%

Functions of the APP gene family in the nervous system: insights from mouse models

2011

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The amyloid precursor protein (APP) plays a key role in the pathogenesis of Alzheimer's disease (AD), as proteolytical cleavage of APP gives rise to the β-amyloid peptide which is deposited in the brains of Alzheimer patients. During the past years, intense research efforts have been directed at elucidating the physiological function(s) of APP and the question of whether a perturbation of these functions contributes to AD pathogenesis. Indeed, a growing body of evidence has accumulated supporting a role of APP and the two closely related homologues APLP1 and APLP2 in various aspects of nervous system development and function, in particular, for synapse formation and function. This review summarizes recent insights into the in vivo role of the APP gene family from mice lacking individual or combinations of APP family members, with particular emphasis on recently generated knockin mice to examine the in vivo relevance of distinct functional domains.

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Endogenous secreted amyloid precursor protein-α regulates hippocampal NMDA receptor function, long-term potentiation and spatial memory

Cited by 170 publications

References 55 publications

DrosophilaAmyloid Precursor Protein-Like Is Required for Long-Term Memory

DrosophilaAmyloid Precursor Protein-Like Is Required for Long-Term Memory

Physiological Functions of APP Family Proteins

Functions of the APP gene family in the nervous system: insights from mouse models

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