Amyloid-β Precursor Protein APP Down-Regulation Alters Actin Cytoskeleton-Interacting Proteins in Endothelial Cells

Ristori, Emma; Cicaloni, Vittoria; Salvini, Laura; Tinti, Laura; Tinti, Cristina; Simons, Michael; Corti, Federico; Donnini, Sandra; Ziche, Marina

doi:10.3390/cells9112506

Cited by 16 publications

(14 citation statements)

References 63 publications

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“…Accordingly, BBB integrity may be disrupted in some of the patients with SZ, causing BBB leakage. Additionally, the imbalances observed in BECs-related growth factors in SZ [61 ▪▪ ,71 ▪▪ ,77 ▪▪ ,79 ▪ ,82,83] might be translated into an altered BBB integrity and function after stressful events [75].…”

Section: Discussionmentioning

confidence: 99%

“…In 2020, a meta-analysis reported unaltered MCP1 blood levels among drug-naive first-episode SZ ( [72,73]. Amyloid precursor protein (APP) is highly expressed in murine endothelium during the first stages of embryogenesis [74] and in-vitro studies indicated a positive effect of APP on endothelial cells migration, proliferation [75] and nitric oxide production [76]. CSF measurements of 11 different growth factors associated with neuro-plasticity indicated lower levels of APP and GDNF in SZ (94 SZ and 118 controls) [77 && ].…”

Section: Evidence From Peripheral and Cerebrospinal Fluid Markersmentioning

confidence: 99%

“…CSF measurements of 11 different growth factors associated with neuro-plasticity indicated lower levels of APP and GDNF in SZ (94 SZ and 118 controls) [77 && ]. Of note, Human Umbilical Vein Endothelial Cells (HUVEC) lacking APP presented four times increase in permeability to FITC-dextran in the presence of an IL-1b stimulus compared to control HUVEC, suggesting a more sensitive endothelial barrier function to inflammation in the absence of APP [75].…”

Section: Evidence From Peripheral and Cerebrospinal Fluid Markersmentioning

confidence: 99%

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Brain vasculature disturbance in schizophrenia

Puvogel

Palma

Sommer

2022

Current Opinion in Psychiatry

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Purpose of reviewThe vascular hypothesis of schizophrenia (SZ) postulates that brain endothelial dysfunction contributes to brain pathophysiology. This review discusses recent evidence for and against this hypothesis, including data related to blood–brain barrier (BBB), brain endothelium, and brain blood supply, to provide a critical weighed update.Recent findingsDifferent studies report a consistent proportion of SZ patients showing increased BBB permeability, reflected by higher levels of albumin in the cerebral spinal fluid. Of note, this was not a result of antipsychotic medication. The high inflammatory profile observed in some SZ patients is strongly associated with increased BBB permeability to circulating immune cells, and with more severe cognitive deficiencies. Also, sex was found to interact with BBB integrity and permeability in SZ. The strongest independent genetic association with SZ has been identified in FZD1, a hypoxia-response gene that is 600-fold higher expressed in early development endothelium as compared to adult brain endothelium. Regarding brain blood supply, there is evidence to suggest alterations in proper brain perfusion in SZ. Nonetheless, ex-vivo experiments suggested that widely used antipsychotics favor vasoconstriction; thus, alterations in cerebral perfusion might be related to the patients′ medication.SummaryIn some patients with SZ, a vulnerable brain endothelium may be interacting with environmental stressors, such as inflammation or hypoxia, converging into a more severe SZ symptomatology. Gene expression and performance of human brain endothelium could vary along with development and the establishment of the BBB; therefore, we encourage to investigate its possible contribution to SZ considering this dynamic context.

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Section: Discussionmentioning

confidence: 99%

Section: Evidence From Peripheral and Cerebrospinal Fluid Markersmentioning

confidence: 99%

Section: Evidence From Peripheral and Cerebrospinal Fluid Markersmentioning

confidence: 99%

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Brain vasculature disturbance in schizophrenia

Puvogel

Palma

Sommer

2022

Current Opinion in Psychiatry

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“…Studies in multiple cell types suggest that APP regulates integrin-mediated adhesion, a function consistent with the ubiquitous expression of both proteins. The loss of APP in endothelial cells reduces expression of β1-and β3-integrins, compromising attachment of cells to collagen and fibronectin substrates ( Ristori et al, 2020 ). Adhesion of THP-1 monocytes to collagen substrates is also dependent on APP expression, wherein adhesion induces the formation of a receptor complex containing β1-integrins and APP, initiating MAPK signaling and facilitating monocyte activation ( Sondag and Combs, 2004 ) ( Figure 4A iii).…”

Section: Interactions Of Cams With App and The Role That Cams Play In...mentioning

confidence: 99%

Amyloid precursor protein (APP) and amyloid β (Aβ) interact with cell adhesion molecules: Implications in Alzheimer’s disease and normal physiology

Pfundstein

Nikonenko

Sytnyk

2022

Front. Cell Dev. Biol.

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Alzheimer’s disease (AD) is an incurable neurodegenerative disorder in which dysfunction and loss of synapses and neurons lead to cognitive impairment and death. Accumulation and aggregation of neurotoxic amyloid-β (Aβ) peptides generated via amyloidogenic processing of amyloid precursor protein (APP) is considered to play a central role in the disease etiology. APP interacts with cell adhesion molecules, which influence the normal physiological functions of APP, its amyloidogenic and non-amyloidogenic processing, and formation of Aβ aggregates. These cell surface glycoproteins also mediate attachment of Aβ to the neuronal cell surface and induce intracellular signaling contributing to Aβ toxicity. In this review, we discuss the current knowledge surrounding the interactions of cell adhesion molecules with APP and Aβ and analyze the evidence of the critical role these proteins play in regulating the processing and physiological function of APP as well as Aβ toxicity. This is a necessary piece of the complex AD puzzle, which we should understand in order to develop safe and effective therapeutic interventions for AD.

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“…For instance, integrins recruit their cytoplasmic adaptors (e.g., kindlin and talin) via a cytoplasmic NPxY motif, and this event ultimately affects the remodeling of the actin cytoskeleton 42 . Similarly, the NPxY-binding APP intracellular adaptors converge to the same cytoskeletal actin pathway 4,23 (table 1). Notably, APOE lipoprotein receptors also recruit the same NPxY motif for signaling (as shall be discussed in the next sections).…”

Section: App May Be a Synaptic Adhesion Molecule: The Evolutionarily-conserved Npxy Motifmentioning

confidence: 99%

An Amyloid Agnostic Reformulation of the Alzheimer’s Disease: The Long Gene Vulnerability Hypothesis

Soheili-Nezhad¹

2021

Preprint

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Alzheimer’s disease (AD) is a genetically complex senile neurodegeneration with unknown etiology. The first gene discovered to be mutated in early-onset AD, the amyloid precursor protein (APP), has been widely assumed as a causal factor in the disease cascade due to its generation of Aβ species. APP has an evolutionarily conserved biological role and activates a signaling program with notable similarities to integrin—a cell adhesion receptor with a wide array of functions. Intriguingly, several AD genome-wide association study (GWAS) candidate genes, including the SHARPIN locus recently reported by us and others, influence signaling of the integrin pathway. Integrins are focal adhesion regulators and serve in nervous system development, synaptic plasticity, and Tau phosphorylation. These observations suggest that the function of APP probably goes beyond Aβ generation in AD. Aging—the strongest risk factor for AD—is associated with various clock-like events in cells. For instance, neurons are continuously impacted by stochastic ‘hits’ to their genomes in aging, in the forms of DNA damage, insertion-deletions, copy-number variations (CNVs) and other types of somatic mutations. DNA damage and somatic mutations can result in neoplastic changes and cancer in mitotically active cells. However, their consequences in post-mitotic cells such as aging neurons are less defined. The current hypothesis holds that the stochastic loss of DNA sequence data at random loci in aging affects longer genes by chance more frequently. As a result, the biological processes coordinated by long genes may be more vulnerable to such random aging effects. Curiously, as shown by us and others, long genes are strongly enriched for synapse- and cell adhesion-related ontologies, more than any other biological process or cellular compartment. In addition, among various cell types, neurons possess the highest levels of long gene expression and are therefore more vulnerable to such harmful effects. The long gene vulnerability hypothesis provides a simple link between aging and the genetic landscape of AD and warrants new strategies for disease modification.

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Amyloid-β Precursor Protein APP Down-Regulation Alters Actin Cytoskeleton-Interacting Proteins in Endothelial Cells

Cited by 16 publications

References 63 publications

Brain vasculature disturbance in schizophrenia

Brain vasculature disturbance in schizophrenia

Amyloid precursor protein (APP) and amyloid β (Aβ) interact with cell adhesion molecules: Implications in Alzheimer’s disease and normal physiology

An Amyloid Agnostic Reformulation of the Alzheimer’s Disease: The Long Gene Vulnerability Hypothesis

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