The Role of APP in Structural Spine Plasticity

Montagna, Elena; Dorostkar, Mario M.; Herms, Jochen

doi:10.3389/fnmol.2017.00136

Cited by 39 publications

(29 citation statements)

References 93 publications

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“…In addition, increasing levels of the secreted APPα (sAPPα, an alternative cleavage product of APP that has neuroprotective and neurotrophic properties) completely reversed deficits in LTP and spatial memory tasks in APP Swe /PS1 E9 mice (Tan et al, 2018). Therefore, it is important to keep in mind the protective roles of some biproducts of APP (for a review see Montagna et al, 2017), although the pathological biproducts of APP are often the focus in AD literature. Together these studies demonstrate potential for therapeutics that target LTP and its downstream pathways using a range of different methods to provide behavioral improvements.…”

Section: Changes In Synaptic Plasticitymentioning

confidence: 99%

Hippocampal Deficits in Amyloid-β-Related Rodent Models of Alzheimer’s Disease

2020

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Alzheimer's disease (AD) is a progressive neurodegenerative disease that is the most common cause of dementia. Symptoms of AD include memory loss, disorientation, mood and behavior changes, confusion, unfounded suspicions, and eventually, difficulty speaking, swallowing, and walking. These symptoms are caused by neuronal degeneration and cell loss that begins in the hippocampus, and later in disease progression spreading to the rest of the brain. While there are some medications that alleviate initial symptoms, there are currently no treatments that stop disease progression. Hippocampal deficits in amyloid-β-related rodent models of AD have revealed synaptic, behavioral and circuit-level defects. These changes in synaptic function, plasticity, neuronal excitability, brain connectivity, and excitation/inhibition imbalance all have profound effects on circuit function, which in turn could exacerbate disease progression. Despite, the wealth of studies on AD pathology we don't yet have a complete understanding of hippocampal deficits in AD. With the increasing development of in vivo recording techniques in awake and freely moving animals, future studies will extend our current knowledge of the mechanisms underpinning how hippocampal function is altered in AD, and aid in progression of treatment strategies that prevent and/or delay AD symptoms.

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Section: Changes In Synaptic Plasticitymentioning

confidence: 99%

Hippocampal Deficits in Amyloid-β-Related Rodent Models of Alzheimer’s Disease

2020

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“…While the acute treatment with Aβ oligomers promotes synaptic receptor dysfunction, chronic treatment results in abnormal spine morphology, with the induction of long thin spines that, ultimately, cause a significant decrease in spine density (Lacor et al, 2007). Alternatively, evidence indicates that extracellular Aβ depends on intracellular Aβ for synaptotoxicity as follows: Aβ binds to APP with high affinity (Lorenzo et al, 2000;Lu et al, 2003;Lacor et al, 2004;Fogel et al, 2014;Wang et al, 2017); extracellular Aβ can promote its processing and intracellular Aβ accumulation (Tampellini et al, 2009); APP enriched at synapses can be the synaptic receptor for Aβ (Laßek et al, 2013;Del Prete et al, 2014;Fanutza et al, 2015;Montagna et al, 2017); APP KO neurons are resistant to exogenous Aβ toxicity (Wang et al, 2017); and, extracellular synthetic Aβ no longer reduces PSD-95 when Aβ production is inhibited (Tampellini et al, 2009).…”

Section: Aβ-direct Impact On Synaptic Traffickingmentioning

confidence: 99%

Intracellular Trafficking Mechanisms of Synaptic Dysfunction in Alzheimer’s Disease

Perdigão

Barata

Araújo

et al. 2020

Front. Cell. Neurosci.

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Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by progressive memory loss. Although AD neuropathological hallmarks are extracellular amyloid plaques and intracellular tau tangles, the best correlate of disease progression is synapse loss. What causes synapse loss has been the focus of several researchers in the AD field. Synapses become dysfunctional before plaques and tangles form. Studies based on early-onset familial AD (eFAD) models have supported that synaptic transmission is depressed by β-amyloid (Aβ) triggered mechanisms. Since eFAD is rare, affecting only 1% of patients, research has shifted to the study of the most common late-onset AD (LOAD). Intracellular trafficking has emerged as one of the pathways of LOAD genes. Few studies have assessed the impact of trafficking LOAD genes on synapse dysfunction. Since endocytic traffic is essential for synaptic function, we reviewed Aβ-dependent and independent mechanisms of the earliest synaptic dysfunction in AD. We have focused on the role of intraneuronal and secreted Aβ oligomers, highlighting the dysfunction of endocytic trafficking as an Aβ-dependent mechanism of synapse dysfunction in AD. Here, we reviewed the LOAD trafficking genes APOE4, ABCA7, BIN1, CD2AP, PICALM, EPH1A, and SORL1, for which there is a synaptic link. We conclude that in eFAD and LOAD, the earliest synaptic dysfunctions are characterized by disruptions of the presynaptic vesicle exo-and endocytosis and of postsynaptic glutamate receptor endocytosis. While in eFAD synapse dysfunction seems to be triggered by Aβ, in LOAD, there might be a direct synaptic disruption by LOAD trafficking genes. To identify promising therapeutic targets and biomarkers of the earliest synaptic dysfunction in AD, it will be necessary to join efforts in further dissecting the mechanisms used by Aβ and by LOAD genes to disrupt synapses.

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“…Furthermore, all of these proteins are reportedly co-localized at the synapse, where metals are abundantly present, and which is a major site of degenerative change in these diseases. Although some APP reportedly is present in the postsynaptic membrane and regulates spine formation [90], it is primarily localized to the presynaptic membrane [91]. PrP C is localized to the postsynaptic membrane with receptors [92], and α-synuclein is mainly found in the presynaptic cytosol.…”

Section: Hypothesis: Loss Of Normal Regulatory Functions Of Amyloidogmentioning

confidence: 99%

Amyloids: Regulators of Metal Homeostasis in the Synapse

2020

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Conformational changes in amyloidogenic proteins, such as β-amyloid protein, prion proteins, and α-synuclein, play a critical role in the pathogenesis of numerous neurodegenerative diseases, including Alzheimer’s disease, prion disease, and Lewy body disease. The disease-associated proteins possess several common characteristics, including the ability to form amyloid oligomers with β-pleated sheet structure, as well as cytotoxicity, although they differ in amino acid sequence. Interestingly, these amyloidogenic proteins all possess the ability to bind trace metals, can regulate metal homeostasis, and are co-localized at the synapse, where metals are abundantly present. In this review, we discuss the physiological roles of these amyloidogenic proteins in metal homeostasis, and we propose hypothetical models of their pathogenetic role in the neurodegenerative process as the loss of normal metal regulatory functions of amyloidogenic proteins. Notably, these amyloidogenic proteins have the capacity to form Ca2+-permeable pores in membranes, suggestive of a toxic gain of function. Therefore, we focus on their potential role in the disruption of Ca2+ homeostasis in amyloid-associated neurodegenerative diseases.

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The Role of APP in Structural Spine Plasticity

Cited by 39 publications

References 93 publications

Hippocampal Deficits in Amyloid-β-Related Rodent Models of Alzheimer’s Disease

Hippocampal Deficits in Amyloid-β-Related Rodent Models of Alzheimer’s Disease

Intracellular Trafficking Mechanisms of Synaptic Dysfunction in Alzheimer’s Disease

Amyloids: Regulators of Metal Homeostasis in the Synapse

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