Novel Insights into the Physiological Function of the APP (Gene) Family and Its Proteolytic Fragments in Synaptic Plasticity

Ludewig, Susann; Körte, Martin

doi:10.3389/fnmol.2016.00161

Cited by 48 publications

(41 citation statements)

References 125 publications

(232 reference statements)

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“…This study completes the set of APP family E2 structures and will assist in our understanding of the structure: function relationships between the APP family members. A combination of biochemical, cellular, and whole‐animal studies indicates that APP, APLP1, and APLP2 have both shared and distinct activities in neuronal and nonneuronal tissues (2, 3, 5, 7, 10, 11, 22, 47, 51). Of these, APLP2 is essential for survival in the absence of the other APP family paralogues (3, 4, 10), which indicates that it possesses unique activities.…”

Section: Resultsmentioning

confidence: 99%

The crystal structure of amyloid precursor‐like protein 2 E2 domain completes the amyloid precursor protein family

et al. 2019

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The amyloid precursor–like protein 2 (APLP2) molecule is a type I transmembrane protein that is crucial for survival, cell‐cell adhesion, neuronal development, myelination, cancer metastasis, modulation of metal, and glucose and insulin homeostasis. Moreover, the importance of the amyloid precursor protein (APP) family in biology and disease is very well known because of its central role in Alzheimer disease. In this study, we determined the crystal structure of the independently folded E2 domain of APLP2 and compared that with its paralogues APP and APLP2, demonstrating high overall structural similarities. The crystal structure of APLP2 E2 was solved as an antiparallel dimer, and analysis of the protein interfaces revealed a distinct mode of dimerization that differs from the previously reported dimerization of either APP or APLP1. Analysis of the APLP2 E2 metal binding sites suggested it binds zinc and copper in a similar manner to APP and APLP1. The structure of this key protein might suggest a relationship between the distinct mode of dimerization and its biologic functions.—Roisman, L. C., Han, S., Chuei, M. J., Connor, A. R., Cappai, R. The crystal structure of amyloid precursor‐like protein 2 E2 domain completes the amyloid precursor protein family. FASEB J. 33, 5076–5081 (2019). http://www.fasebj.org

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Section: Resultsmentioning

confidence: 99%

The crystal structure of amyloid precursor‐like protein 2 E2 domain completes the amyloid precursor protein family

et al. 2019

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“…; Baumkotter et al . ; Ludewig & Korte ). It has been described that part of the synaptogenic function of APP is carried out through its interaction with the scaffold proteins X11/Mint which recognizes the YENPTY cytoplasmic domain of APP as well as of others synaptic adhesion molecules like Neurexins (Borg et al .…”

Section: The Role Of App In Synaptogenesis and Dendrite Spine Morphologymentioning

confidence: 99%

The physiological role of the amyloid precursor protein as an adhesion molecule in the developing nervous system

Sosa

Cáceres

Dupraz

et al. 2017

Journal of Neurochemistry

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The amyloid precursor protein (APP) is a type I transmembrane glycoprotein better known for its participation in the physiopathology of Alzheimer disease as the source of the beta amyloid fragment. However, the physiological functions of the full length protein and its proteolytic fragments have remained elusive. APP was first described as a cell-surface receptor; nevertheless, increasing evidence highlighted APP as a cell adhesion molecule. In this review, we will focus on the current knowledge of the physiological role of APP as a cell adhesion molecule and its involvement in key events of neuronal development, such as migration, neurite outgrowth, growth cone pathfinding, and synaptogenesis. Finally, since APP is over-expressed in Down syndrome individuals because of the extra copy of chromosome 21, in the last section of the review, we discuss the potential contribution of APP to the neuronal and synaptic defects described in this genetic condition. This Review followed a CAEN Return Home grant.

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“…Does Aβ40 being more abundant play a different physiological role from Aβ42? Other products of APP processing, as well as APP full length, also have synaptic physiological functions that have been recently reviewed (Ludewig and Korte, 2016).…”

Section: Aβ Physiological Role At Synapsesmentioning

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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Novel Insights into the Physiological Function of the APP (Gene) Family and Its Proteolytic Fragments in Synaptic Plasticity

Cited by 48 publications

References 125 publications

The crystal structure of amyloid precursor‐like protein 2 E2 domain completes the amyloid precursor protein family

The crystal structure of amyloid precursor‐like protein 2 E2 domain completes the amyloid precursor protein family

The physiological role of the amyloid precursor protein as an adhesion molecule in the developing nervous system

Intracellular Trafficking Mechanisms of Synaptic Dysfunction in Alzheimer’s Disease

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