The <scp>N</scp>‐terminal fragment of the β‐amyloid precursor protein of <scp>A</scp>lzheimer's disease (<scp>N‐APP</scp>) binds to phosphoinositide‐rich domains on the surface of hippocampal neurons

Dawkins, Edgar; Gasperini, Robert; Hu, Yanling; Cui, Hao; Vincent, Amanda; Bolós, Marta; Young, Karen; Foa, Lisa; Small, David H.

doi:10.1002/jnr.23422

Cited by 6 publications

(1 citation statement)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The identification of additional Aβ peptides—both N-terminally truncated (e.g., Aβ 5–X ) and N-terminally extended [ 74 , 75 ]—and APP N-terminal fragments (e.g., N-APP 18–286 fragment) [ 76 , 77 ] in human CSF suggests that APP could be proteolytically cleaved by additional secretases. Different caspases—namely caspase-3, caspase-6 and caspase-8 (reviewed in [ 58 ])—can mediate APP C-terminal domain cleavage at D664.…”

Section: Amyloid Precursor Protein: Structure Expression and Processingmentioning

confidence: 99%

The Labyrinthine Landscape of APP Processing: State of the Art and Possible Novel Soluble APP-Related Molecular Players in Traumatic Brain Injury and Neurodegeneration

Masi

Biundo

Fiou

et al. 2023

IJMS

View full text Add to dashboard Cite

Amyloid Precursor Protein (APP) and its cleavage processes have been widely investigated in the past, in particular in the context of Alzheimer’s Disease (AD). Evidence of an increased expression of APP and its amyloidogenic-related cleavage enzymes, β-secretase 1 (BACE1) and γ-secretase, at the hit axon terminals following Traumatic Brain Injury (TBI), firstly suggested a correlation between TBI and AD. Indeed, mild and severe TBI have been recognised as influential risk factors for different neurodegenerative diseases, including AD. In the present work, we describe the state of the art of APP proteolytic processing, underlining the different roles of its cleavage fragments in both physiological and pathological contexts. Considering the neuroprotective role of the soluble APP alpha (sAPPα) fragment, we hypothesised that sAPPα could modulate the expression of genes of interest for AD and TBI. Hence, we present preliminary experiments addressing sAPPα-mediated regulation of BACE1, Isthmin 2 (ISM2), Tetraspanin-3 (TSPAN3) and the Vascular Endothelial Growth Factor (VEGFA), each discussed from a biological and pharmacological point of view in AD and TBI. We finally propose a neuroprotective interaction network, in which the Receptor for Activated C Kinase 1 (RACK1) and the signalling cascade of PKCβII/nELAV/VEGF play hub roles, suggesting that vasculogenic-targeting therapies could be a feasible approach for vascular-related brain injuries typical of AD and TBI.

show abstract

Section: Amyloid Precursor Protein: Structure Expression and Processingmentioning

confidence: 99%

The Labyrinthine Landscape of APP Processing: State of the Art and Possible Novel Soluble APP-Related Molecular Players in Traumatic Brain Injury and Neurodegeneration

Masi

Biundo

Fiou

et al. 2023

IJMS

View full text Add to dashboard Cite

show abstract

Soluble Amyloid Precursor Protein Alpha Interacts with alpha3-Na, K-ATPAse to Induce Axonal Outgrowth but Not Neuroprotection: Evidence for Distinct Mechanisms Underlying these Properties

et al. 2017

View full text Add to dashboard Cite

Amyloid precursor protein (APP) is cleaved not only to generate the amyloid peptide (Aß), involved in neurodegenerative processes, but can also be metabolized by alpha secretase to produce and release soluble N-terminal APP (sAPPα), which has many properties including the induction of axonal elongation and neuroprotection. The mechanisms underlying the properties of sAPPα are not known. Here, we used proteomic analysis of mouse cortico-hippocampal membranes to identify the neuronal specific alpha3 (α3)-subunit of the plasma membrane enzyme Na, K-ATPase (NKA) as a new binding partner of sAPPα. We showed that sAPPα recruits very rapidly clusters of α3-NKA at neuronal surface, and its binding triggers a cascade of events promoting sAPPα-induced axonal outgrowth. The binding of sAPPα with α3-NKA was not observed for sAPPα-induced Aß1-42 oligomers neuroprotection, neither the downstream events particularly the interaction of sAPPα with APP before endocytosis, ERK signaling, and the translocation of SET from the nucleus to the plasma membrane. These data suggest that the mechanisms of the axonal growth promoting and neuroprotective properties of sAPPα appear to be specific and independent. The signals at the cell surface specific to trigger these mechanisms require further study.

show abstract

A Greek Tragedy: The Growing Complexity of Alzheimer Amyloid Precursor Protein Proteolysis

Andrew

Kellett

Wang

et al. 2016

Journal of Biological Chemistry

150

122

View full text Add to dashboard Cite

Proteolysis of the amyloid precursor protein (APP) liberates various fragments including the proposed initiator of Alzheimer disease-associated dysfunctions, amyloid-␤. However, recent evidence suggests that the accepted view of APP proteolysis by the canonical ␣-, ␤-, and ␥-secretases is simplistic, with the discovery of a number of novel APP secretases (including ␦-and -secretases, alternative ␤-secretases) and additional metabolites, some of which may also cause synaptic dysfunction. Furthermore, various proteins have been identified that interact with APP and modulate its cleavage by the secretases. Here, we give an overview of the increasingly complex picture of APP proteolysis.Currently over 46 million people worldwide are living with dementia (see the Alzheimer's Disease International website) with Alzheimer disease (AD) 3 representing the most common form of dementia. In AD, the amyloid cascade hypothesis posits that amyloid-␤ (A␤), produced through the sequential proteolytic cleavage of the amyloid precursor protein (APP) by the ␤-and ␥-secretases, is a key molecule in initiating and propagating disease pathology including neurofibrillary tangle formation, neuronal cell loss, aberrant synaptic activity, and brain atrophy that lead to the clinically recognized symptoms of dementia (1). However, identification of the A␤ peptide 25 years ago has not yet led to the advent of a viable therapeutic strategy that can slow or halt the progression of AD. Recent studies have revealed new complexities in the proteolytic processing of APP, including the identification of novel secretases which generate APP metabolites that accumulate in the brains of AD patients and may contribute to the synaptic dysfunction observed in the disease. In addition, numerous proteins are being identified that interact with APP, modulating its proteolysis and A␤ production. These new APP secretases and metabolites, along with the APP interactors, may present novel therapeutic targets that are independent of direct modulation of the canonical secretases and that will need to be considered when evaluating the results from current A␤-directed therapies. In this Minireview, we summarize the recent developments in APP proteolysis focusing on the novel secretases, APP interactors, and APP metabolites that are impacting on our understanding of both APP biology and the neurodegenerative disease process. The Canonical ␣-, ␤-, and ␥-Secretases and APP FragmentsThe generally accepted model of APP proteolysis is that APP is processed by one of two distinct proteolytic pathways (Fig. 1A). In the amyloidogenic pathway, ␤-secretase, the ␤-site APP-cleaving enzyme 1 (BACE1), cleaves APP within the ectodomain and liberates a soluble proteolytic fragment, termed soluble APP␤ (sAPP␤), primarily in the endosomal system from the transmembrane APP holoprotein (2). The remaining C-terminal membrane-bound APP fragment, CTF␤, is subsequently cleaved by the presenilin (PS)-containing ␥-secretase multisubunit complex to liberate the A␤ peptide and the APP intrace...

show abstract

The N‐terminal fragment of the β‐amyloid precursor protein of Alzheimer's disease (N‐APP) binds to phosphoinositide‐rich domains on the surface of hippocampal neurons

Cited by 6 publications

References 49 publications

The Labyrinthine Landscape of APP Processing: State of the Art and Possible Novel Soluble APP-Related Molecular Players in Traumatic Brain Injury and Neurodegeneration

The Labyrinthine Landscape of APP Processing: State of the Art and Possible Novel Soluble APP-Related Molecular Players in Traumatic Brain Injury and Neurodegeneration

Soluble Amyloid Precursor Protein Alpha Interacts with alpha3-Na, K-ATPAse to Induce Axonal Outgrowth but Not Neuroprotection: Evidence for Distinct Mechanisms Underlying these Properties

A Greek Tragedy: The Growing Complexity of Alzheimer Amyloid Precursor Protein Proteolysis

Contact Info

Product

Resources

About