Role of APP for dendritic spine formation and stability

Jung, Christian; Herms, Jochen

doi:10.1007/s00221-011-2939-x

Cited by 25 publications

(20 citation statements)

References 45 publications

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“…The major affects of APP in the formation of spines appeared at the early stages of the disease, depending on the model used and the region of the brain studied (Belichenko et al, 2004;Bittner et al, 2009;Mucke et al, 2000;Perez-Cruz et al, 2011;Priller et al, 2006;Simon et al, 2009;Villar et al, 2005). Nevertheless, when APP expression is either eliminated or augmented in aged animals, spine density decreases in the hippocampus (Jung and Herms, 2012). The latter observation is in agreement with clinical data showing that in brains of patients suffering from AD, the number of synapses is decreased and synapse loss is a major hallmark of the disease (DeKosky and Scheff, 1990;Terry et al, 1991).…”

Section: Synaptic Loss In Alzheimer's Diseasementioning

confidence: 95%

“…However, APP may affect dendritic spine formation in mouse brain (reviewed in (Jung and Herms, 2012)). Studies show that lack of APP leads to increased dendritic spine density (Bittner et al, 2009;Priller et al, 2006) and overexpression of human APP sometimes causes decreased formation of dendritic spines (Belichenko et al, 2004;Mucke et al, 2000;Perez-Cruz et al, 2011;Simon et al, 2009;Villar et al, 2005).…”

Section: Synaptic Loss In Alzheimer's Diseasementioning

confidence: 99%

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Presenilins, Deranged Calcium Homeostasis, Synaptic Loss and Dysfunction in Alzheimer's Disease

Попугаева¹,

Supnet²,

Bezprozvanny³

et al. 2012

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Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder affecting millions of people. Synaptic dysfunction and physical loss of synapses are responsible for memory impairments in AD. The molecular mechanisms responsible for synaptic loss in AD are not understood. The main risk factor for sporadic AD (SAD) is advanced age. Missense mutations in presenilin (PS) proteins and in amyloid precursor protein (APP) are responsible for majority of rare familial AD (FAD) cases. Increased production of A 42 amyloidogenic peptide occurs in SAD and FAD. Synaptotoxic effects of A 42 may be linked to synaptic loss in AD. FAD mutations in PS proteins disrupt endoplasmic reticulum (ER) calcium (Ca 2+ ) leak function of PSs and result in increased Ca 2+ levels in neuronal ER. Similar increases in neuronal ER Ca 2+ levels occur in aging neurons. Increased neuronal ER Ca 2+ levels lead to a compensatory upregulation of ER Ca 2+ release channels, the ryanodine receptors (RyanR), and downregulation of the synaptic store-operated Ca 2+ entry (SOC) pathway. In this review we propose a hypothesis that excessive Ca 2+ release from the ER and insufficient SOC Ca 2+ entry lead to destabilization and eventual elimination of mature mushroom spines in PS-FAD neurons and in aging SAD neurons. The proposed Ca 2+ -dependent spine destabilization mechanism may act in parallel or synergistically with A 42 synaptotoxicity mechanisms. The proposed model may help to establish a cause-and-effect connection between abnormal Ca 2+ and amyloid homeostasis and synaptic loss in AD.

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Section: Synaptic Loss In Alzheimer's Diseasementioning

confidence: 95%

Section: Synaptic Loss In Alzheimer's Diseasementioning

confidence: 99%

Presenilins, Deranged Calcium Homeostasis, Synaptic Loss and Dysfunction in Alzheimer's Disease

Попугаева¹,

Supnet²,

Bezprozvanny³

et al. 2012

messenger

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“…Transgenic APP overexpression decreased spine density in aged animals, whereas prior to the onset of plaque deposition increases in spine density were observed (reviewed in [16]). Conversely, age APP-KO mice showed alterations in dendritic arborization [14] and reduced spine densities on dendrites of cortical and hippocampal neurons [17].…”

Section: Introductionmentioning

confidence: 99%

Comparative analysis of single and combined APP/APLP knockouts reveals reduced spine density in APP-KO mice that is prevented by APPsα expression

Weyer

Zagrebelsky

Herrmann

et al. 2014

acta neuropathol commun

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Synaptic dysfunction and synapse loss are key features of Alzheimer’s pathogenesis. Previously, we showed an essential function of APP and APLP2 for synaptic plasticity, learning and memory. Here, we used organotypic hippocampal cultures to investigate the specific role(s) of APP family members and their fragments for dendritic complexity and spine formation of principal neurons within the hippocampus. Whereas CA1 neurons from APLP1-KO or APLP2-KO mice showed normal neuronal morphology and spine density, APP-KO mice revealed a highly reduced dendritic complexity in mid-apical dendrites. Despite unaltered morphology of APLP2-KO neurons, combined APP/APLP2-DKO mutants showed an additional branching defect in proximal apical dendrites, indicating redundancy and a combined function of APP and APLP2 for dendritic architecture. Remarkably, APP-KO neurons showed a pronounced decrease in spine density and reductions in the number of mushroom spines. No further decrease in spine density, however, was detectable in APP/APLP2-DKO mice. Mechanistically, using APPsα-KI mice lacking transmembrane APP and expressing solely the secreted APPsα fragment we demonstrate that APPsα expression alone is sufficient to prevent the defects in spine density observed in APP-KO mice. Collectively, these studies reveal a combined role of APP and APLP2 for dendritic architecture and a unique function of secreted APPs for spine density.

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“…There are evidences that suggest that APP interacts with the calcium sensor of synaptic vesicles possibly regulating synaptic vesicle exocytosis, and calcium homeostasis [31,32]. The role of APP in learning and memory has been evidenced by studies showing that regulation of its levels of expression can modulate synaptic spine density, an effect that is mediated by its soluble α-cleaved fragment sAPPα [33,34]. APP is also essential for the synapses and required for spatial learning and long-term potentiation (LTP, which correlate with memory formation) [35].…”

Section: App and Aβ As Modulators Of Synaptic Activitymentioning

confidence: 99%

Physiological Role of Amyloid Beta in Neural Cells: The Cellular Trophic Activity

Cárdenas-Aguayo¹,

Silva-Lucero²,

Cortés-Ortiz³

et al. 2014

Neurochemistry

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Role of APP for dendritic spine formation and stability

Cited by 25 publications

References 45 publications

Presenilins, Deranged Calcium Homeostasis, Synaptic Loss and Dysfunction in Alzheimer's Disease

Presenilins, Deranged Calcium Homeostasis, Synaptic Loss and Dysfunction in Alzheimer's Disease

Comparative analysis of single and combined APP/APLP knockouts reveals reduced spine density in APP-KO mice that is prevented by APPsα expression

Physiological Role of Amyloid Beta in Neural Cells: The Cellular Trophic Activity

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