Amyloid-beta mediates homeostatic synaptic plasticity

Abstract

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 ...

Aβ/Amyloid Precursor Protein-Induced Hyperexcitability and Dysregulation of Homeostatic Synaptic Plasticity in Neuron Models of Alzheimer’s Disease

“…Interestingly, we observed that the mean firing rates were similar between TTX, vehicle and bicuculline treated WT neurons after 48 h consistent with findings suggesting that while single unit firing is unstable, networks maintain surprisingly stable firing frequencies (Slomowitz et al, 2015). Aβ and APP have been implicated in normal HSP (Gilbert et al, 2016;Galanis et al, 2021), and APP/PS1 mice were recently shown to have defective downscaling during sleep (Zarhin et al, 2022). Defective HSP could help explain why AD transgenic mice are more susceptible to pharmacologically-induced and spontaneous seizures (Minkeviciene et al, 2009;Reyes-Marin and Nuñez, 2017) and could provide a framework for explaining the increased sensitivity to seizures in AD patients (Pandis and Scarmeas, 2012).…”

“…Structural homeostatic synaptic plasticity is known to occur at three main locations: (1) at the post-synapse involving reduced or increased levels of surface receptors (Turrigiano et al, 1998) ; (2) at the axon initial segment (AIS) by either increasing or decreasing its length or by shifting the AIS further out into the axon (Wefelmeyer et al, 2016); or (3) at the pre-synapse by modifying how much neurotransmitter is stored in synaptic vesicles or through homeostatic maintenance of presynaptic exocytosis (Delvendahl et al, 2019). Of note, Aβ was suggested to overshoot normal homeostatic scaling in response to sensory deprivation in vivo or TTX-mediated inhibition in vitro (Gilbert et al, 2016), and Aβ was recently shown to regulate homeostatic synaptic upscaling after activity blockade in dentate gyrus in vivo (Galanis et al, 2021). Our findings that APP/PS1 neurons do not increase their activity after 48 h of TTX treatment nor decrease firing rate after 48 h of bicuculline treatment suggest that Aβ/APP play important roles not only in adjusting to activity blockade but also have roles in homeostatic downscaling in response to excessive activity.…”

“…These modulatory processes enable neuronal communication to be maintained within an appropriate window, allowing meaningful information transfer (Turrigiano, 2012). Recently, both APP and Aβ were implicated in the regulation of HSP (Gilbert et al, 2016;Galanis et al, 2021), indicating that these proteins play important roles beyond AD pathophysiology. Further, prior in vivo work in AD transgenic mice has suggested that HSP mechanisms might be impaired, since chronic hypo-or hyper-activity via either long term sleep deprivation or induction, or unilateral whisker removal, conditions in which HSP should be engaged, negatively impacted AD transgenic compared to wild-type (WT) mice (Kang et al, 2009;Tampellini et al, 2010).…”

Alzheimer’s disease as a syndrome of overloaded amyloidic synaptic tagging in memory networks

“…Nehls commented that the effect of Aβ on memory is dose dependent with higher concentrations "preserving new memory traces from being overridden by subsequent events that are to be memorized", though the basis of this statement was not elaborated (Nehls, 2016). Many studies implicate Aβ in metaplastic events (Galanis et al, 2020;Gilbert et al, 2016;Jang and Chung, 2016;Li et al, 2017a;Megill et al, 2015;Peineau et al, 2018) and Puzzo's group suggest that by inducing conversion of early LTP to late LTP, oAβ42 plays a part in synaptic tagging (Gulisano et al, 2019). Parihar and Brewer emphasize the modulatory effects of Aβ on neuroplasticity, noting that aging and Aβ independently decrease neuronal plasticity, also pointing out that Aβ-induced neurotoxicity is age-dependent and that the longevity of humans may contribute to AD by rendering the brain vulnerable to Aβ-induced neurotoxicity (Parihar and Brewer, 2010).…”

“…To many, these findings substantiate the view that Aβ42 acts largely with sinister intentions. However, there is increasing recognition that Aβ42 and other APP-derivatives play important beneficial roles in modulating synaptic plasticity (Li et al, 2017b;Morley et al, 2019;Parihar and Brewer, 2010;Puzzo et al, 2012;Ricciarelli and Fedele, 2018;Venkitaramani et al, 2007) including metaplastic events such as STC and synaptic scaling (Galanis et al, 2020;Gilbert et al, 2016;Jang and Chung, 2016;Li et al, 2017a;Megill et al, 2015;Peineau et al, 2018). This is not to say that Aβ42 is always harmless (see section 21), indeed there is little doubt Aβ42 can be very toxic at certain concentrations and in certain forms.…”