Deletion of the amyloid precursor-like protein 2 (APLP2) does not affect hippocampal neuron morphology or function

Midthune, Brea; Tyan, Sheue-Houy; Walsh, Jessica J.; Sarsoza, Floyd; Eggert, Simone; Hof, Patrick R.; Dickstein, Dara L.; Koo, Edward H.

doi:10.1016/j.mcn.2012.02.001

Cited by 32 publications

(30 citation statements)

References 49 publications

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“…Although no compensatory changes in APLP1 or APLP2 expression were detected in 14 weeks old APP−/− mice (Zheng et al, 1995), it is not clear whether there is a reduction in expression of the APP orthologs with age. In this regard, a parallel study in APLP2 failed to detect any changes in dendritic morphology or spine density in either young or old animals (Midthune et al, 2012), a situation that is quite different from what we saw in the present study. Consequently, it will be interesting to determine whether there is an age-associated reduction in the expression or levels of APLP1 or APLP2.…”

Section: Discussioncontrasting

confidence: 99%

Amyloid precursor protein (APP) regulates synaptic structure and function

Tyan

Shih

Walsh

et al. 2012

Molecular and Cellular Neuroscience

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153

146

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The amyloid precursor protein (APP) plays a critical role in Alzheimer’s disease (AD) pathogenesis. APP is proteolytically cleaved by β- and γ-secretases to generate the amyloid β-protein (Aβ), the core protein component of senile plaques in AD. It is also cleaved by α-secretase to release the large soluble APP (sAPP) luminal domain that has been shown to exhibit trophic properties. Increasing evidence points to the development of synaptic deficits and dendritic spine loss prior to deposition of amyloid in transgenic mouse models that overexpress APP and Aβ peptides. The consequence of loss of APP, however, is unsettled. In this study, we investigated whether APP itself plays a role in regulating synaptic structure and function using an APP knock-out (APP−/−) mouse model. We examined dendritic spines in primary cultures of hippocampal neurons and CA1 neurons of hippocampus from APP−/− mice. In the cultured neurons, there was a significant decrease (~35%) in spine density in neurons derived from APP−/− mice compared to littermate control neurons that were partially restored with sAPPα-conditioned medium. In APP−/− mice in vivo, spine numbers were also significantly reduced but by a smaller magnitude (~15%). Furthermore, apical dendritic length and dendritic arborization were markedly diminished in hippocampal neurons. These abnormalities in neuronal morphology were accompanied by reduction in long-term potentiation. Strikingly, all these changes in vivo were only seen in mice that were 12-15 months in age but not in younger animals. We propose that APP, specifically sAPP, is necessary for the maintenance of dendritic integrity in the hippocampus in an age-associated manner. Finally, these age-related changes may contribute to Alzheimer’s changes independent of Aβ-mediated synaptic toxicity.

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Section: Discussioncontrasting

confidence: 99%

Amyloid precursor protein (APP) regulates synaptic structure and function

Tyan

Shih

Walsh

et al. 2012

Molecular and Cellular Neuroscience

Self Cite

153

146

View full text Add to dashboard Cite

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“…APP and APLP2 are ubiquitously expressed in the nervous tissue and at the neuromuscular junction (NMJ, Slunt et al, 1994; Lorent et al, 1995) as well as in pyramidal and GABAergic neurons of the hippocampus and cortex (Wang et al, 2014; Hick et al, 2015). In contrast to APP-KO mice, young and aged APLP2 single KOs behave like wild-type mice showing no impairments in LTP, STP, PPF, or basal synaptic transmission (Weyer et al, 2011; Midthune et al, 2012). These observations go in line with normal learning and memory performance in cognitive tasks like the Morris-Water-Maze (MWM) or the passive avoidance test (Heber et al, 2000; Guo et al, 2012).…”

Section: Role Of Full-length App Proteins At the Synapsementioning

confidence: 99%

“…The functional effects are consistent with investigations of dendritic spine numbers at excitatory neurons, reflecting the number of excitatory synapses. Whereas, the spine density assessed in vivo was affected in aged APP-KO animals, it was unaltered in APLP2-KO mice as well as in APLP2 OHCs in vitro (Lee et al, 2010; Midthune et al, 2012; Weyer et al, 2014). It seems likely that endogenous APP is able to compensate for the genetic ablation of APLP2 with age, while vice versa APLP2 is incapable to compensate the loss of APP in aged animals.…”

Section: Role Of Full-length App Proteins At the Synapsementioning

confidence: 99%

Novel Insights into the Physiological Function of the APP (Gene) Family and Its Proteolytic Fragments in Synaptic Plasticity

Ludewig

Körte

2017

Front. Mol. Neurosci.

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The amyloid precursor protein (APP) is well known to be involved in the pathophysiology of Alzheimer's disease (AD) via its cleavage product amyloid ß (Aß). However, the physiological role of APP, its various proteolytic products and the amyloid precursor-like proteins 1 and 2 (APLP1/2) are still not fully clarified. Interestingly, it has been shown that learning and memory processes represented by functional and structural changes at synapses are altered in different APP and APLP1/2 mouse mutants. In addition, APP and its fragments are implicated in regulating synaptic strength further reinforcing their modulatory role at the synapse. While APLP2 and APP are functionally redundant, the exclusively CNS expressed APLP1, might have individual roles within the synaptic network. The proteolytic product of non-amyloidogenic APP processing, APPsα, emerged as a neurotrophic peptide that facilitates long-term potentiation (LTP) and restores impairments occurring with age. Interestingly, the newly discovered η-secretase cleavage product, An-α acts in the opposite direction, namely decreasing LTP. In this review we summarize recent findings with emphasis on the physiological role of the APP gene family and its proteolytic products on synaptic function and plasticity, especially during processes of hippocampal LTP. Therefore, we focus on literature that provide electrophysiological data by using different mutant mouse strains either lacking full-length or parts of the APP proteins or that utilized secretase inhibitors as well as secreted APP fragments.

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“…Major insights into the physiological functions of APP and the related APLPs (APP like proteins) were obtained from knockout models (Mü ller et al, 2017). While most impairments of APP-KO mice emerged only in aged mice (Dawson et al, 1999;Seabrook et al, 1999;Ring et al, 2007;Lee et al, 2010;Tyan et al, 2012), combined APP/APLP2 double knockout mice die shortly after birth, likely due to severe deficits at the neuromuscular junction (von Koch et al, 1997;Heber et al, 2000;Wang et al, 2005;Klevanski et al, 2014). Recently generated forebrain-specific double knockout mice (termed NexCre cDKO), that lack APP from embryonic day 11.5 onwards in excitatory forebrain neurons on a global constitutive APLP2-KO background, showed a severe synaptic phenotype already at young age, including reduced spine density and impaired LTP in the hippocampus, as well as deficits in learning and memory (Hick et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Distinct in vivo roles of secreted APP ectodomain variants APP sα and APP sβ in regulation of spine density, synaptic plasticity, and cognition

et al. 2018

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Increasing evidence suggests that synaptic functions of the amyloid precursor protein (APP), which is key to Alzheimer pathogenesis, may be carried out by its secreted ectodomain (APPs). The specific roles of APPsα and APPsβ fragments, generated by non-amyloidogenic or amyloidogenic APP processing, respectively, remain however unclear. Here, we expressed APPsα or APPsβ in the adult brain of conditional double knockout mice (cDKO) lacking APP and the related APLP2. APPsα efficiently rescued deficits in spine density, synaptic plasticity (LTP and PPF), and spatial reference memory of cDKO mice. In contrast, APPsβ failed to show any detectable effects on synaptic plasticity and spine density. The C-terminal 16 amino acids of APPsα (lacking in APPsβ) proved sufficient to facilitate LTP in a mechanism that depends on functional nicotinic α7-nAChRs. Further, APPsα showed high-affinity, allosteric potentiation of heterologously expressed α7-nAChRs in oocytes. Collectively, we identified α7-nAChRs as a crucial physiological receptor specific for APPsα and show distinct roles for APPsα versus APPsβ. This implies that reduced levels of APPsα that might occur during Alzheimer pathogenesis cannot be compensated by APPsβ.

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Deletion of the amyloid precursor-like protein 2 (APLP2) does not affect hippocampal neuron morphology or function

Cited by 32 publications

References 49 publications

Amyloid precursor protein (APP) regulates synaptic structure and function

Amyloid precursor protein (APP) regulates synaptic structure and function

Novel Insights into the Physiological Function of the APP (Gene) Family and Its Proteolytic Fragments in Synaptic Plasticity

Distinct in vivo roles of secreted APP ectodomain variants APP sα and APP sβ in regulation of spine density, synaptic plasticity, and cognition

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