Synaptopodin Deficiency Ameliorates Symptoms in the 3xTg Mouse Model of Alzheimer's Disease

Aloni, Etay; Oni-Biton, Efrat; Tsoory, Michael; Moallem, Dalia H.; Segal, Menahem

doi:10.1523/jneurosci.2920-18.2019

Cited by 18 publications

(15 citation statements)

References 39 publications

(52 reference statements)

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“…It may be important to mention in this context that changes in synaptopodin expression have been reported in brain tissue from AD subjects (Reddy et al, 2005) and synaptopodin has been recently linked to autophagy of phospho-MAPT/Tau (Ji et al, 2019). Moreover, a reduction in synaptopodin expression seems to ameliorate symptoms in a transgenic mouse model of AD (Aloni et al, 2019).…”

Section: Discussionmentioning

confidence: 95%

Amyloid-beta mediates homeostatic synaptic plasticity

Galanis

Fellenz

Becker

et al. 2020

Preprint

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The physiological role of the amyloid-precursor protein (APP) is insufficiently understood. 29 Recent work has implicated APP in the regulation of synaptic plasticity. Substantial evidence 30 exists for a role of APP and its secreted ectodomain APPsα in Hebbian plasticity. Here, we 31 addressed the relevance of APP in homeostatic synaptic plasticity using organotypic tissue 32 cultures of APP -/mice. In the absence of APP, dentate granule cells failed to strengthen their 33 excitatory synapses homeostatically. Homeostatic plasticity is rescued by amyloid- (A and 34 not by APPsα, and it is neither observed in APP +/+ tissue treated with or -secretase 35 inhibitors nor in synaptopodin-deficient cultures lacking the Ca 2+ -dependent molecular 36 machinery of the spine apparatus. Together, these results suggest a role of APP processing via 37 the amyloidogenic pathway in homeostatic synaptic plasticity, representing a function of 38 relevance for brain physiology as well as for brain states associated with increased A levels. 39Hebbian plasticity, homeostatic plasticity 41 82 and report an essential role of Aβ in homeostatic plasticity of excitatory neurotransmission, 83 suggesting that this could be one of the major physiological functions of Aβ in the normal 84 brain. 85 5 RESULTSHomeostatic synaptic plasticity is not observed in dentate granule cells of APP-deficient 86 entorhinal-hippocampal tissue cultures 87 Considering the role of the hippocampal formation and specifically the dentate gyrus in 88 memory formation (Aimone et al., 2011; Friedman and Goldman-Rakic, 1988), 3-week-old 89 (18 days in vitro; div) organotypic tissue cultures containing the entorhinal cortex and the 90 hippocampus were prepared from APP +/+ and APP -/mice-including age-and time-matched 91 APP +/+ littermates obtained from APP +/intercrossing ( Figure 1A, B). Tissue cultures were 92 treated with tetrodotoxin (TTX; 2 µM; 2 days) to induce homeostatic synaptic plasticity, and 93 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated 94 miniature excitatory postsynaptic currents (mEPSCs) were recorded from individual dentate 95 granule cells (Figure 1C) to assess compensatory (i.e., homeostatic) synaptic changes. 96 In line with previous work [e.g., (Echegoyen et al., 2007; Kim and Tsien, 2008; Strehl et 97 al., 2018; Turrigiano et al., 1998; Vlachos et al., 2013)], a homeostatic increase in excitatory 98 synaptic strength (i.e., a robust increase in mEPSC amplitudes) was observed in the wild-type 99 tissue cultures (Figure 1D, E). In APP -/preparations, no significant changes in mEPSC 100properties were observed in dentate granule cells ( Figure 1F, G). Specifically, mean mEPSC 101 amplitude was 11.5 ± 0.3 pA in vehicle-only-treated and 11.8 ± 0.4 pA TTX-treated APP -/-102 dentate granule cells (p = 0.4; Mann-Whitney-test). 103In an attempt to rescue the ability of granule cells to express homeostatic synaptic 104 plasticity, APP -/tissue cultures were transfected with a bicistronic adeno-associated ...

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Section: Discussionmentioning

confidence: 95%

Amyloid-beta mediates homeostatic synaptic plasticity

Galanis

Fellenz

Becker

et al. 2020

Preprint

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“…RyRs play an important role in Ca 2+ regulation, and RyR dysfunction is implicated in the Ca 2+ dysregulation observed in AD [ 1 ]. RyR expression and RyR mediated Ca 2+ responses are increased in the soma and dendritic spines of hippocampal and cortical pyramidal neurons of AD mice expressing PS1 mutations ( Figure 1 and Figure 2 ) [ 9 , 30 , 127 ], effects which are normalized by acute or chronic treatment with dantrolene, a negative allosteric RyR modulator [ 50 , 114 ]. In particular, the RyR2 isoform, which is overexpressed in the hippocampus of AD mice [ 30 , 114 ], plays an important role in maintenance of synaptic function [ 128 ] and shortening of the RyR2 mean channel open time reverses the synaptic dysfunction and Ca 2+ dyshomeostasis observed in an AD mouse model [ 47 ].…”

Section: Ca 2+ Dysregulation and Synaptic Defecmentioning

confidence: 99%

Ca2+ Dyshomeostasis Disrupts Neuronal and Synaptic Function in Alzheimer’s Disease

McDaid

Mustaly-Kalimi

Stutzmann

2020

Cells

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Ca2+ homeostasis is essential for multiple neuronal functions and thus, Ca2+ dyshomeostasis can lead to widespread impairment of cellular and synaptic signaling, subsequently contributing to dementia and Alzheimer’s disease (AD). While numerous studies implicate Ca2+ mishandling in AD, the cellular basis for loss of cognitive function remains under investigation. The process of synaptic degradation and degeneration in AD is slow, and constitutes a series of maladaptive processes each contributing to a further destabilization of the Ca2+ homeostatic machinery. Ca2+ homeostasis involves precise maintenance of cytosolic Ca2+ levels, despite extracellular influx via multiple synaptic Ca2+ channels, and intracellular release via organelles such as the endoplasmic reticulum (ER) via ryanodine receptor (RyRs) and IP3R, lysosomes via transient receptor potential mucolipin channel (TRPML) and two pore channel (TPC), and mitochondria via the permeability transition pore (PTP). Furthermore, functioning of these organelles relies upon regulated inter-organelle Ca2+ handling, with aberrant signaling resulting in synaptic dysfunction, protein mishandling, oxidative stress and defective bioenergetics, among other consequences consistent with AD. With few effective treatments currently available to mitigate AD, the past few years have seen a significant increase in the study of synaptic and cellular mechanisms as drivers of AD, including Ca2+ dyshomeostasis. Here, we detail some key findings and discuss implications for future AD treatments.

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“…It may be important to mention in this context that changes in synaptopodin expression have been reported in brain tissue from AD subjects ( Reddy et al, 2005 ), and synaptopodin has been recently linked to autophagy of phospho-MAPT/Tau ( Ji et al, 2019 ). Moreover, a reduction in synaptopodin expression seems to ameliorate symptoms in a transgenic mouse model of AD ( Aloni et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Amyloid-Beta Mediates Homeostatic Synaptic Plasticity

et al. 2021

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The physiological role of the amyloid-precursor protein (APP) is insufficiently understood.Recent work has implicated APP in the regulation of synaptic plasticity. Substantial evidence exists for a role of APP and its secreted ectodomain APPsα in Hebbian plasticity. Here, we addressed the relevance of APP in homeostatic synaptic plasticity using organotypic tissue cultures prepared from APP -/mice of both sexes. In the absence of APP, dentate granule cells failed to strengthen their excitatory synapses homeostatically. Homeostatic plasticity is rescued by amyloid-(A and not by APPsα, and it is neither observed in APP +/+ tissue treated with -or -secretase inhibitors nor in synaptopodin-deficient cultures lacking the Ca 2+ -dependent molecular machinery of the spine apparatus. Together, these results suggest a role of APP processing via the amyloidogenic pathway in homeostatic synaptic plasticity, representing a function of relevance for brain physiology as well as for brain states associated with increased A levels. SIGNIFICANCE STATEMENTConsiderable effort has been directed to better understand the pathogenic role of the Amyloid Precursor Protein (APP) and its cleavage products in neurodegeneration -with a major focus on the accumulation and deposition of "synaptotoxic" Aβ peptides, which are produced by sequential cleavage of APP by β-and γ-secretases. Although the amyloidogenic APP processing pathway has recently been targeted in patients with Alzheimer's Diseases, the physiological role of APP/Aβ remains unclear, which limits our understanding how such interventions could influence brain functions in health and disease. Here, we report an essential role of Aβ (and not APPsα) in homeostatic synaptic plasticity, suggesting that this could be a major physiological function of Aβ in the healthy brain.

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Synaptopodin Deficiency Ameliorates Symptoms in the 3xTg Mouse Model of Alzheimer's Disease

Cited by 18 publications

References 39 publications

Amyloid-beta mediates homeostatic synaptic plasticity

Amyloid-beta mediates homeostatic synaptic plasticity

Ca2+ Dyshomeostasis Disrupts Neuronal and Synaptic Function in Alzheimer’s Disease

Amyloid-Beta Mediates Homeostatic Synaptic Plasticity

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