Cleavage of Alzheimer's Amyloid Precursor Protein by α-Secretase Occurs at the Surface of Neuronal Cells

Parvathy, S.; Hussain, Ishrut; Karran, Eric; Turner, and Anthony J.; Hooper, Nigel M.

doi:10.1021/bi9906827

Cited by 185 publications

(156 citation statements)

References 49 publications

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“…Several reports support a principally cell surface localization for ␣-secretase activity (40,41). By two different approaches, we demonstrate an inhibition of APP endocytosis and an increased amount of APP on the cell surface after cholesterol depletion with M␤CD.…”

Section: Discussionsupporting

confidence: 71%

Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the α-secretase ADAM 10

Kojro

Gimpl

Lammich

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

754

616

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Biochemical, epidemiological, and genetic findings demonstrate a link between cholesterol levels, processing of the amyloid precursor protein (APP), and Alzheimer's disease. In the present report, we identify the ␣-secretase ADAM 10 (a disintegrin and metalloprotease) as a major target of the cholesterol effects on APP metabolism. Treatment of various peripheral and neural cell lines with either the cholesterol-extracting agent methyl-␤-cyclodextrin or the hydroxymethyl glutaryl-CoA reductase inhibitor lovastatin resulted in a drastic increase of secreted ␣-secretase cleaved soluble APP. This strong stimulatory effect was in the range obtained with phorbol esters and was further increased in cells overexpressing ADAM 10. In cells overexpressing APP, the increase of ␣-secretase activity resulted in a decreased secretion of A␤ peptides. Several mechanisms were elucidated as being the basis of enhanced ␣-secretase activity: increased membrane fluidity and impaired internalization of APP were responsible for the effect observed with methyl-␤-cyclodextrin; treatment with lovastatin resulted in higher expression of the ␣-secretase ADAM 10. Our results demonstrate that cholesterol reduction promotes the nonamyloidogenic ␣-secretase pathway and the formation of neuroprotective ␣-secretase cleaved soluble APP by several mechanisms and suggest approaches to prevention of or therapy for Alzheimer's disease.A myloid-␤ peptides (A␤), the principal proteinaceous components of amyloid plaques in brains of Alzheimer's disease (AD) patients, are derived from proteolytic cleavage of the amyloid precursor protein (APP), a type I integral membrane protein that is ubiquitously expressed. Both during and after its transport through the secretory pathway to the surface of cultured cells, a fraction of APP molecules undergoes specific endoproteolytic cleavage, most frequently by a scission between amino acids 16 and 17 of the A␤ region (1). This principal secretory cleavage is effected by (a) protease(s) designated as ␣-secretase(s). Soluble N-terminal APP fragments of 105-125 kDa are released into vesicle lumens and from the cell surface; similar species are readily detected in human plasma and cerebrospinal fluid (2). Recently, evidence has been provided that members of the ADAM family (a disintegrin and metalloprotease) act as ␣-secretases (3-5). For ADAM 10, basal and protein kinase C-stimulated ␣-secretase activity and many properties expected for the proteolytic processing of APP have been found (4).The stimulation of ␣-secretase activity and an increase of ␣-secretase cleaved soluble APP (APPs␣) might be beneficial for the treatment of AD for several reasons. In principle, proteolytic cleavage of APP within the A␤ sequence precludes the formation of the amyloid peptides derived from alternative proteolysis of APP with the ␤-secretase cleaving at the N terminus and the ␥-secretase(s) at the C terminus of A␤ peptides (for a recent review of APP processing, see ref. 6). On the other hand, APPs␣ has trophic effects on cerebral neuro...

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Section: Discussionsupporting

confidence: 71%

Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the α-secretase ADAM 10

Kojro

Gimpl

Lammich

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

754

616

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“…As the presence of NTF-NgR in the lysate was abolished by BFA treatment, the cleavage of NgR must be instigated after the receptor is trafficked from the ER compartment but prior to it reaching the cell surface. This scenario is similar to that for the release of APP by α-secretase, where cleavage occurs both at the cell surface and in the trans-Golgi compartment of the secretory pathway (Parvathy et al, 1999;Skovronsky et al, 2000).…”

Section: Discussionsupporting

confidence: 53%

Zinc metalloproteinase-mediated cleavage of the human Nogo-66 receptor

Walmsley

McCombie

Neumann

et al. 2004

Journal of Cell Science

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The central nervous system myelin components oligodendrocyte-myelin glycoprotein, myelin-associated glycoprotein and the Nogo-66 domain of Nogo-A inhibit neurite outgrowth by binding the neuronal glycosyl-phosphatidylinositol-anchored Nogo-66 receptor (NgR) that transduces the inhibitory signal to the cell interior via a transmembrane co-receptor, p75NTR. Here, we demonstrate that human NgR expressed in human neuroblastoma cells is constitutively cleaved in a post-ER compartment to generate a lipid-raft associated C-terminal fragment that is present on the cell surface and a soluble N-terminal fragment that is released into the medium. Mass spectrometric analysis demonstrated that the N-terminal fragment terminated just after the C-terminus of the ligand-binding domain of NgR. In common with other shedding mechanisms, the release of this fragment was blocked by a hydroxamate-based inhibitor of zinc metalloproteinases, but not by inhibitors of other protease classes and up-regulated by treatment with the cellular cholesterol depleting agent methyl-β-cyclodextrin. The N-terminal fragment bound Nogo-66 and blocked Nogo-66 binding to cell surface NgR but failed to associate with p75NTR, indicative of a role as a Nogo-66 antagonist. Furthermore, the N- and C-terminal fragments of NgR were detectable in human brain cortex and the N-terminal fragment was also present in human cerebrospinal fluid, demonstrating that NgR proteolysis occurs within the human nervous system. Our findings thus identify a potential cellular mechanism for the regulation of NgR function at the level of the receptor.

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“…It is conceivable that the Reelin-APP interaction is required to promote α-cleavage of APP (Parvathy et al, 1999) and neurite outgrowth (Hoe et al, 2009). …”

Section: Dysfunctional Reelin Signaling and Its Role In Ad Etiologymentioning

confidence: 99%

Decisive role of Reelin signaling during early stages of Alzheimer’s disease

et al. 2013

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Alzheimer's disease (AD) is one of the largest unmet medical concerns of our society. Around 25 million patients worldwide together with their families are still waiting for an effective treatment. We have recently initiated a re-evaluation of our knowledge of the molecular and cellular mechanisms underlying sporadic AD. Based on the existing literature, we have proposed a mechanistic explanation of how the late-onset form of the disease may evolve on the cellular level. Here, we expand this hypothesis by addressing the pathophysiological changes underlying the early and almost invariant appearance of the neurofibrillary tangles, the only reliable correlate of the cognitive status, in distinct brain areas and their consistent "spread" along interconnected neurons as the disease advances. In this review we present and discuss novel evidence that the extracellular signaling protein Reelin, expressed along the olfactory and limbic pathways in the adult brain, might hold a key to understand the earliest steps of the disease, highlighting the olfactory pathway as the brain's Achilles heel involved in the initiation of the pathophysiological characteristic of late-onset AD. AbstractAlzheimer`s disease (AD) is one of the largest unmet medical needs of our society. Around 25 million patients worldwide together with their families are still waiting for an effective treatment. We have recently initiated a re-evaluation of our knowledge of the molecular and cellular mechanisms underlying sporadic AD. Based on the existing literature, we have proposed a mechanistic explanation of how the late-onset form of the disease may evolve on the cellular level. Here, we expand this hypothesis by addressing the pathophysiological changes underlying the early and almost invariant appearance of the neurofibrillary tangles (NFTs), the only reliable correlate of the cognitive status, in distinct brain areas and their consistent "spread" along interconnected neurons as the disease advances. In this review we present and discuss novel evidence that the extracellular signaling protein Reelin, expressed along the olfactory and limbic pathways in the adult brain, might hold a key to understand the earliest steps of the disease, highlighting the olfactory pathway as the brain's Achilles heel involved in the initiation of the pathophysiology characteristic of late-onset AD.3

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Cleavage of Alzheimer's Amyloid Precursor Protein by α-Secretase Occurs at the Surface of Neuronal Cells

Cited by 185 publications

References 49 publications

Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the α-secretase ADAM 10

Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the α-secretase ADAM 10

Zinc metalloproteinase-mediated cleavage of the human Nogo-66 receptor

Decisive role of Reelin signaling during early stages of Alzheimer’s disease

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