The intramembrane protease γ-secretase is a hetero-tetrameric protein complex with presenilin as the catalytic subunit and cleaves its membrane protein substrates within their single transmembrane ...domains. γ-Secretase is well known for its role in Notch signalling and in Alzheimer’s disease, where it catalyzes the formation of the pathogenic amyloid β (Aβ) peptide. However, in the 21 years since its discovery many more substrates and substrate candidates of γ-secretase were identified. Although the physiological relevance of the cleavage of many substrates remains to be studied in more detail, the substrates demonstrate a broad role for γ-secretase in embryonic development, adult tissue homeostasis, signal transduction and protein degradation. Consequently, chronic γ-secretase inhibition may cause significant side effects due to inhibition of cleavage of multiple substrates. This review provides a list of 149 γ-secretase substrates identified to date and highlights by which expeirmental approach substrate cleavage was validated. Additionally, the review lists the cleavage sites where they are known and discusses the functional implications of γ-secretase cleavage with a focus on substrates identified in the recent past, such as CHL1, TREM2 and TNFR1. A comparative analysis demonstrates that γ-secretase substrates mostly have a long extracellular domain and require ectodomain shedding before γ-secretase cleavage, but that γ-secretase is also able to cleave naturally short substrates, such as the B cell maturation antigen. Taken together, the list of substrates provides a resource that may help in the future development of drugs inhibiting or modulating γ-secretase activity in a substrate-specific manner.
Proteolytic removal of membrane protein ectodomains (ectodomain shedding) is a post‐translational modification that controls levels and function of hundreds of membrane proteins. The contributing ...proteases, referred to as sheddases, act as important molecular switches in processes ranging from signaling to cell adhesion. When deregulated, ectodomain shedding is linked to pathologies such as inflammation and Alzheimer's disease. While proteases of the “a disintegrin and metalloprotease” (ADAM) and “beta‐site APP cleaving enzyme” (BACE) families are widely considered as sheddases, in recent years a much broader range of proteases, including intramembrane and soluble proteases, were shown to catalyze similar cleavage reactions. This review demonstrates that shedding is a fundamental process in cell biology and discusses the current understanding of sheddases and their substrates, molecular mechanisms and cellular localizations, as well as physiological functions of protein ectodomain shedding. Moreover, we provide an operational definition of shedding and highlight recent conceptual advances in the field. While new developments in proteomics facilitate substrate discovery, we expect that shedding is not a rare exception, but rather the rule for many membrane proteins, and that many more interesting shedding functions await discovery.
This review gives an operational definition of shedding as a fundamental cell biological and (patho)physiological process, and summarizes our current understanding of sheddases and their substrates, mechanisms and roles.
J. Neurochem. (2011) 116, 10-21. ABSTRACT: Ectodomain shedding of the amyloid precursor protein (APP) by the metalloprotease activity α-secretase is a key regulatory event preventing the generation ...of the Alzheimer's disease (AD) amyloid β peptide. Proteases similar to α-secretase are essential for diverse physiological processes, such as embryonic development, cell adhesion and neuronal guidance. Previously, several proteases were suggested as candidate α-secretases for APP, in particular members of the ADAM family (a disintegrin and metalloprotease). Two recent studies analyzed primary neurons, which are the cell type affected in AD, and finally demonstrated that the constitutively cleaving α-secretase activity is selectively mediated by ADAM10. An increase in α-secretase cleavage is considered a therapeutic approach for AD. However, the molecular mechanisms regulating α-secretase cleavage remain only partly understood. Signaling pathways activating protein kinase C and MAP kinase play a central role in stimulating α-secretase cleavage of APP. Additionally, several recent publications demonstrate that ADAM10 expression and α-secretase cleavage of APP are tightly controlled at the level of transcription, e.g. by retinoic acid receptors and sirtuins, and at the level of translation and protein trafficking. This review focuses on the recent progress made in unraveling the molecular identity, regulation and therapeutic potential of α-secretase in Alzheimer's disease.
Proteins belonging to the 'A Disintegrin And Metalloproteinase' (ADAM) family are membrane-anchored proteases that are able to cleave the extracellular domains of several membrane-bound proteins in a ...process known as 'ectodomain shedding'. In the central nervous system, ADAM10 has attracted the most attention, since it was described as the amyloid precursor protein α-secretase over ten years ago. Despite the excitement over the potential of ADAM10 as a novel drug target in Alzheimer disease, the physiological functions of ADAM10 in the brain are not yet well understood. This is largely because of the embryonic lethality of ADAM10-deficient mice, which results from the loss of cleavage and signaling of the Notch receptor, another ADAM10 substrate. However, the recent generation of conditional ADAM10-deficient mice and the identification of further ADAM10 substrates in the brain has revealed surprisingly numerous and fundamental functions of ADAM10 in the development of the embryonic brain and also in the homeostasis of adult neuronal networks. Mechanistically, ADAM10 controls these functions by utilizing unique postsynaptic substrates in the central nervous system, in particular synaptic cell adhesion molecules, such as neuroligin-1, N-cadherin, NCAM, Ephrin A2 and A5. Consequently, a dysregulation of ADAM10 activity is linked to psychiatric and neurological diseases, such as epilepsy, fragile X syndrome and Huntington disease. This review highlights the recent progress in understanding the substrates and function as well as the regulation and cell biology of ADAM10 in the central nervous system and discusses the value of ADAM10 as a drug target in brain diseases.
Coding variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are associated with late-onset Alzheimer's disease (AD). We demonstrate that amyloid plaque seeding is increased in the ...absence of functional Trem2. Increased seeding is accompanied by decreased microglial clustering around newly seeded plaques and reduced plaque-associated apolipoprotein E (ApoE). Reduced ApoE deposition in plaques is also observed in brains of AD patients carrying TREM2 coding variants. Proteomic analyses and microglia depletion experiments revealed microglia as one origin of plaque-associated ApoE. Longitudinal amyloid small animal positron emission tomography demonstrates accelerated amyloidogenesis in Trem2 loss-of-function mutants at early stages, which progressed at a lower rate with aging. These findings suggest that in the absence of functional Trem2, early amyloidogenesis is accelerated due to reduced phagocytic clearance of amyloid seeds despite reduced plaque-associated ApoE.
The protease β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is required for the production of the amyloid-β (Aβ) peptide, which is central to the pathogenesis of Alzheimer's disease ...(AD). Chronic inhibition of this protease may temper amyloid production and cure or prevent AD. However, while BACE1 inhibitors are being pushed forward as drug candidates, a remarkable gap in knowledge on the physiological functions of BACE1 and its close homolog BACE2 becomes apparent. Here we discuss the major discoveries of the past 3 years concerning BACE1 biology and to what extent these could limit the use of BACE1 inhibitors in the clinic.
‘A disintegrin and metalloproteases’ (ADAMs) are a family of transmembrane proteins with diverse functions in multicellular organisms. About half of the ADAMs are active metalloproteases and cleave ...numerous cell surface proteins, including growth factors, receptors, cytokines and cell adhesion proteins. The other ADAMs have no catalytic activity and function as adhesion proteins or receptors. Some ADAMs are ubiquitously expressed, others are expressed tissue specifically. This review highlights functions of ADAMs in the mammalian nervous system, including their links to diseases. The non-proteolytic ADAM11, ADAM22 and ADAM23 have key functions in neural development, myelination and synaptic transmission and are linked to epilepsy. Among the proteolytic ADAMs, ADAM10 is the best characterized one due to its substrates Notch and amyloid precursor protein, where cleavage is required for nervous system development or linked to Alzheimer’s disease (AD), respectively. Recent work demonstrates that ADAM10 has additional substrates and functions in the nervous system and its substrate selectivity may be regulated by tetraspanins. New roles for other proteolytic ADAMs in the nervous system are also emerging. For example, ADAM8 and ADAM17 are involved in neuroinflammation. ADAM17 additionally regulates neurite outgrowth and myelination and its activity is controlled by iRhoms. ADAM19 and ADAM21 function in regenerative processes upon neuronal injury. Several ADAMs, including ADAM9, ADAM10, ADAM15 and ADAM30, are potential drug targets for AD. Taken together, this review summarizes recent progress concerning substrates and functions of ADAMs in the nervous system and their use as drug targets for neurological and psychiatric diseases.
J. Neurochem. (2011) 117, 779–796.
Regulated intramembrane proteolysis (RIP) controls the communication between cells and the extracellular environment. RIP is essential in the nervous system, but ...also in other tissues. In the RIP process, a membrane protein typically undergoes two consecutive cleavages. The first one results in the shedding of its ectodomain. The second one occurs within its transmembrane domain, resulting in secretion of a small peptide and the release of the intracellular domain into the cytosol. The proteolytic cleavage fragments act as versatile signaling molecules or are further degraded. An increasing number of membrane proteins undergo RIP. These include growth factors, cytokines, cell adhesion proteins, receptors, viral proteins and signal peptides. A dysregulation of RIP is found in diseases, such as leukemia and Alzheimer’s disease. One of the first RIP substrates discovered was the amyloid precursor protein (APP). RIP processing of APP controls the generation of the amyloid β‐peptide, which is believed to cause Alzheimer’s disease. Focusing on APP as the best‐studied RIP substrate, this review describes the function and mechanism of the APP RIP proteases with the goal to elucidate cellular mechanisms and common principles of the RIP process in general.
α-secretase is the name for a metalloprotease activity, which is assumed to play a key role in the prevention of the molecular mechanisms underlying Alzheimer's disease (AD). Proteases similar to ...α-secretase are essential for a wide range of biological processes, such as cell adhesion and embryonic development. The molecular culprit in AD is the amyloid β peptide (Aβ), which derives from the amyloid precursor protein (APP) through sequential cleavage by the two proteases β- and γ-secretase. In contrast, α-secretase, which is the metalloprotease ADAM10, cleaves APP within the Aβ domain, thus preventing Aβ generation. Additionally, it produces a secreted APP ectodomain with neurotrophic and neuroprotective properties. An increase in α-secretase cleavage is considered a therapeutic approach for AD, but the molecular mechanisms regulating α-secretase cleavage are only partly known. Protein kinase C and mitogen-activated protein kinase constitute central signaling hubs for the regulation of α-secretase cleavage. Additionally, recent studies increasingly demonstrate that the correct spatial and temporal localization of the two membrane proteins APP and α-secretase is essential for efficient α-secretase cleavage of APP. This review highlights the role of signaling pathways and protein trafficking in the control of APP α-secretase cleavage.
Alzheimer disease (AD) is the most common cause of dementia in older individuals (>65 years) and has a long presymptomatic phase. Preventive therapies for AD are not yet available, and potential ...disease-modifying therapies targeting amyloid-β plaques in symptomatic stages of AD have only just been approved in the United States. Small-molecule inhibitors of β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1; also known as β-secretase 1) reduce the production of amyloid-β peptide and are among the most advanced drug candidates for AD. However, to date all phase II and phase III clinical trials of BACE inhibitors were either concluded without benefit or discontinued owing to futility or the occurrence of adverse effects. Adverse effects included early, mild cognitive impairment that was associated with all but one inhibitor; preliminary results suggest that the cognitive effects are non-progressive and reversible. These discontinuations have raised questions regarding the suitability of BACE1 as a drug target for AD. In this Perspective, we discuss the status of BACE inhibitors and suggest ways in which the results of the discontinued trials can inform the development of future clinical trials of BACE inhibitors and related secretase modulators as preventative therapies. We also propose a series of experiments that should be performed to inform 'go-no-go' decisions in future trials with BACE inhibitors and consider the possibility that low levels of BACE1 inhibition could avoid adverse effects while achieving efficacy for AD prevention.
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