The Emerging Role of Tetraspanins in the Proteolytic Processing of the Amyloid Precursor Protein

Abstract

Tetraspanins are a family of ubiquitously expressed and conserved proteins, which are characterized by four transmembrane domains and the formation of a short and a large extracellular loop (LEL). Through interaction with other tetraspanins and transmembrane proteins such as growth factors, receptors and integrins, tetraspanins build a wide ranging and membrane spanning protein network. Such tetraspanin-enriched microdomains (TEMs) contribute to the formation and stability of functional signaling complexes involved in cell activation, adhesion, motility, differentiation, and malignancy. There is increasing evidence showing that the tetraspanins also regulate the proteolysis of the amyloid precursor protein (APP) by physically interacting with the APP secretases. CD9, CD63, CD81, Tspan12, Tspan15 are among the tetraspanins involved in the intracellular transport and in the stabilization of the gamma secretase complex or ADAM10 as the major APP alpha secretase. They also directly regulate, most likely in concert with other tetraspanins, the proteolytic function of these membrane embedded enzymes. Despite the knowledge about the interaction of tetraspanins with the secretases not much is known about their physiological role, their importance in Alzheimer's Disease and their exact mode of action. This review aims to summarize the current knowledge and open questions regarding the biology of tetraspanins and the understanding how these proteins interact with APP processing pathways. Ultimately, it will be of interest if tetraspanins are suitable targets for future therapeutical approaches.

Neuronal calcineurin transcriptional targets parallel changes observed in Alzheimer disease brain

“…); its normal function involved homeostatic cholesterol regulation which is disrupted in AD (Sato and Morishita ). Similarly, Tspan3 plays a role in membrane and cholesterol regulation as well as amyloid precursor protein processing and presenilin function (Seipold and Saftig ). Rasgrf1 is necessary for dendritic spine formation (Detrait et al .…”

“…Nceh1 protects against asynuclein toxicity (Zhang et al 2017) and is decreased in blood samples drawn from AD patients (Mandas et al 2012); its normal function involved homeostatic cholesterol regulation which is disrupted in AD (Sato and Morishita 2015). Similarly, Tspan3 plays a role in membrane and cholesterol regulation as well as amyloid precursor protein processing and presenilin function (Seipold and Saftig 2016). Rasgrf1 is necessary for dendritic spine formation (Detrait et al 2014), and is down-regulated in AD and prion diseases (Tian et al 2014).…”

Presenilins Interactome in Alzheimer’s Disease and Pathological Ageing

“…Tetraspanin-enriched microdomains (TEMs) consist of proteins and lipids crucial for coordination of many biological processes, including cell adhesion, proteolysis, cell motility or sorting to exosomes [66]. A series of proteins transiently interacting with the γ-secretase complex were found in TEM network.…”

The value of CD9 as a prognostic predictor for various human malignant neoplasms: a meta-analysis

“…Tetraspranin is a kind of protein which has four transmembrane domains, a small extracellular loop (termed SEL), a large extracellular loop (known as LEL), and short intracellular N-and C-terminal tails (1). Tetraspanin acts as a cell surface organizer by recruiting particular partner proteins to tetraspanin-enriched micro domains to roll into the meditation of various of cellular activities (2), such as signal transduction, cell growth, cell adhesion, cell motility and differentiation, and sperm-egg fusion (3)(4)(5).…”