APPsα Rescues Tau-Induced Synaptic Pathology

Bold, Charlotte; Baltissen, Danny; Ludewig, Susann; Back, Michaela Kerstin; Just, Jennifer; Kilian, Lara; Erdinger, Susanne; Banićević, Marija; Rehra, Lena; Almouhanna, Fadi; Nigri, Martina; Wolfer, David P; Spilger, Roman; Rohr, Karl; Kann, Oliver; Buchholz, Christian J.; Engelhardt, Jakob von; Körte, Martin; Müller, Ulrike

doi:10.1523/jneurosci.2200-21.2022

Cited by 7 publications

(7 citation statements)

References 80 publications

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“…Bace-1 and Adam10) that results in fragments with distinct functions in regulating neural circuits (Jimenez et al, 2011; Nunan and Small, 2000; Vassar et al, 1999). While Aβ-fragments were mostly linked to pathological conditions (Opazo et al, 2018), neuroprotective and synaptic plasticity enhancing properties have been attributed to soluble APPα (Bold et al, 2022; Fol et al, 2016; Jimenez et al, 2011; Mockett et al, 2017; Richter et al, 2018; Tan et al, 2018). Moreover, recent advances demonstrated that APP and its fragments are regulators of homeostatic synaptic plasticity which aims at keeping neuronal activity in a dynamic range through synaptic adaptations (Galanis et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

The amyloid precursor protein regulates synaptic transmission at medial perforant path synapses

Lenz

Eichler

Kruse

et al. 2022

Preprint

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The perforant path provides the main cortical excitatory input to the hippocampus. Due to its important role in information processing and coding, entorhinal projections to the dentate gyrus have been studied in considerable detail. Nevertheless, a characterization of synaptic transmission between individual connected pairs of entorhinal stellate cells and dentate granule cells is still pending. Here, we have used organotypic entorhino-hippocampal tissue cultures, in which the entorhino-dentate (EC-GC) projection is present and EC-GC pairs can be studied using whole-cell patch clamp recordings. Using cultures of wildtype mice, the properties of EC-GC synapses formed by afferents from the lateral and medial entorhinal cortex were compared and differences in short-term plasticity were revealed. Since the perforant path is severely affected in Alzheimer′s disease, we used cultures of APP-deficient mice to address the role of the amyloid-precursor protein (APP) at this synapse. APP-deficiency caused alterations in excitatory neurotransmission at medial perforant path synapses that were accompanied by transcriptomic and ultrastructural changes. Moreover, the deletion of pre- but not postsynaptic APP through the local injection of Cre-expressing AAVs in conditional APPflox/flox tissue cultures increased the efficacy of neurotransmission at perforant path synapses. Together, these data suggest a physiological role for presynaptic APP at medial perforant path synapses, which may be adversely affected under conditions of altered APP processing.

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Section: Discussionmentioning

confidence: 99%

The amyloid precursor protein regulates synaptic transmission at medial perforant path synapses

Lenz

Eichler

Kruse

et al. 2022

Preprint

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“…Due to the highly plastic nature of synapses, synaptic dysfunction and synapse loss are reversible processes even in the presence of established pathology, which is highly relevant when treating symptomatic patients. Importantly, the rescue of spine density by APPsα is not limited to THY-Tau22 mice, as we recently showed similar spine density restoring properties of APPsα also in Tau transgenic P301S mice ( Bold et al, 2022 ). Moreover, APPsα also normalized spine density under conditions of Aβ plaque pathology ( Fol et al, 2016 ) and in gene targeted mice lacking endogenous APP and APLP2 ( Richter et al, 2018 ), indicating a more general function for synaptic repair.…”

Section: Discussionmentioning

confidence: 70%

“…Sarkosyl-insoluble and sarkosyl-soluble Tau aggregates were separated as described previously (Eckermann et al, 2007;Bold et al, 2022). For the Tau fractionation, mice were sacrificed by cervical 10.3389/fncel.2023.1106176 dislocation 3 months post-injection at 12 months of age and the brain was rapidly removed.…”

Section: Protein Extraction Based On Solubilitymentioning

confidence: 99%

“…APPsα expression in the hippocampus of these mice rescued deficits in synaptic plasticity, spine density and spatial memory ( Fol et al, 2016 ). These results raised the question of whether the beneficial in vivo effects of APPsα may also be exploited for Aβ-independent impairments, in particular Tau-induced pathology ( Bold et al, 2022 ). In this regard, previous studies had indicated that APPsα overexpression in neuroblastoma cells can inhibit GSK3β ( Deng et al, 2015 ) and that incubation of primary neurons with recombinant APPsα (recAPPsα) resulted in downregulation of CDK5 expression and activity ( Hartl et al, 2013 ) in vitro .…”

Section: Introductionmentioning

confidence: 99%

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APPsα rescues CDK5 and GSK3β dysregulation and restores normal spine density in Tau transgenic mice

Baltissen

Bold

Rehra

et al. 2023

Front. Cell. Neurosci.

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The Tau protein can be phosphorylated by numerous kinases. In Alzheimer’s disease (AD) hyperphosphorylated Tau species accumulate as neurofibrillary tangles that constitute a major hallmark of AD. AD is further characterized by extracellular Aβ plaques, derived from the β-amyloid precursor protein APP. Whereas Aβ is produced by amyloidogenic APP processing, APP processing along the competing non-amyloidogenic pathway results in the secretion of neurotrophic and synaptotrophic APPsα. Recently, we demonstrated that APPsα has therapeutic effects in transgenic AD model mice and rescues Aβ-dependent impairments. Here, we examined the potential of APPsα to regulate two major Tau kinases, GSK3β and CDK5 in THY-Tau22 mice, a widely used mouse model of tauopathy. Immunohistochemistry revealed a dramatic increase in pathologically phosphorylated (AT8 and AT180) or misfolded Tau species (MC1) in the hippocampus of THY-Tau22 mice between 3 and 12 months of age. Using a highly sensitive radioactive kinase assay with recombinant human Tau as a substrate and immunoblotting, we demonstrate an increase in GSK3β and CDK5 activity in the hippocampus of THY-Tau22 mice. Interestingly, AAV-mediated intracranial expression of APPsα in THY-Tau22 mice efficiently restored normal GSK3β and CDK5 activity. Western blot analysis revealed upregulation of the CDK5 regulatory proteins p35 and p25, indicating CDK5 hyperactivation in THY-Tau22 mice. Strikingly, AAV-APPsα rescued p25 upregulation to wild-type levels even at stages of advanced Tau pathology. Sarkosyl fractionation used to study the abundance of soluble and insoluble phospho-Tau species revealed increased soluble AT8-Tau and decreased insoluble AT100-Tau species upon AAV-APPsα injection. Moreover, AAV-APPsα reduced misfolded (MC1) Tau species, particularly in somatodendritic compartments of CA1 pyramidal neurons. Finally, we show that AAV-APPsα upregulated PSD95 expression and rescued deficits in spine density of THY-Tau22 mice. Together our findings suggest that APPsα holds therapeutic potential to mitigate Tau-induced pathology.

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“…App, the second protein in the aforementioned list, has also been shown to regulate synaptic maintenance or drive synaptic loss. Two recent studies are particularly relevant in this regard: The first study ( Bold et al, 2022 ) showed that APPsα (the proteolytic cleavage product of APP along the nonamyloidogenic pathway, i.e., the one not producing Aβ) rescued abnormally low spine density in tauopathy model mice, even when applied at nanomolar concentrations. In contrast, the second study ( Lee et al, 2022 ) as well as many others, showed that soluble forms of oligomeric Aβ (the proteolytic APP cleavage product along the amyloidogenic pathway) drove excitatory synapse loss.…”

Section: Discussionmentioning

confidence: 99%

Synapse integrity and function: Dependence on protein synthesis and identification of potential failure points

Cohen

Ziv²,

Ziv

2022

Front. Mol. Neurosci.

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Synaptic integrity and function depend on myriad proteins - labile molecules with finite lifetimes that need to be continually replaced with freshly synthesized copies. Here we describe experiments designed to expose synaptic (and neuronal) properties and functions that are particularly sensitive to disruptions in protein supply, identify proteins lost early upon such disruptions, and uncover potential, yet currently underappreciated failure points. We report here that acute suppressions of protein synthesis are followed within hours by reductions in spontaneous network activity levels, impaired oxidative phosphorylation and mitochondrial function, and, importantly, destabilization and loss of both excitatory and inhibitory postsynaptic specializations. Conversely, gross impairments in presynaptic vesicle recycling occur over longer time scales (days), as does overt cell death. Proteomic analysis identified groups of potentially essential ‘early-lost’ proteins including regulators of synapse stability, proteins related to bioenergetics, fatty acid and lipid metabolism, and, unexpectedly, numerous proteins involved in Alzheimer’s disease pathology and amyloid beta processing. Collectively, these findings point to neuronal excitability, energy supply and synaptic stability as early-occurring failure points under conditions of compromised supply of newly synthesized protein copies.

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APPsα Rescues Tau-Induced Synaptic Pathology

Cited by 7 publications

References 80 publications

The amyloid precursor protein regulates synaptic transmission at medial perforant path synapses

The amyloid precursor protein regulates synaptic transmission at medial perforant path synapses

APPsα rescues CDK5 and GSK3β dysregulation and restores normal spine density in Tau transgenic mice

Synapse integrity and function: Dependence on protein synthesis and identification of potential failure points

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