322 Inhibitors of cathepsin D block β-secretase-like cleavage in human cells

Chevallier, Nathalie; Marambaud, Philippe; Vizzavona, Jean; Baur, C.P.; Spillantini, Maria Grazia; Fulcrand, Pierre; Martinez, J.H.; Goedert, Michel; Vincent, Jean‐Pierre; Checler, Frédéric

doi:10.1016/s0197-4580(96)80324-1

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“…A further acceleration of APP processing is expected if, as we observed, the trafficking to endosomes of appropriate proteases is increased abnormally. In this regard, one of the cathepsins that we monitored in this study, Cat D, has ␤ and ␥ secretase activity toward model peptides and/or recombinant APP (Dreyer et al, 1994;Evin et al, 1995;Higaki et al, 1995;Chevallier et al, 1996). Other cathepsins also indirectly influence A␤ formation (Sahasrabudhe et al, 1993;Bernstein and Wiedanders, 1994;Munger et al, 1995).…”

Section: Implications For ␤-Amyloidogenesis and Pathogenesis In Admentioning

confidence: 92%

Increased Neuronal Endocytosis and Protease Delivery to Early Endosomes in Sporadic Alzheimer’s Disease: Neuropathologic Evidence for a Mechanism of Increased β-Amyloidogenesis

et al. 1997

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The early endosome is the first vacuolar compartment along the endocytic pathway. It is the site of internalization and initial processing of amyloid precursor protein (APP) and apolipoprotein E (ApoE), two proteins of etiological importance in Alzheimer's disease, and a putative site of ␤-amyloid peptide (A␤) formation. Here, we identify early endosomes in human pyramidal neurons, using specific compartmental markers and morphometry, and show that in Alzheimer's disease individual endosomes display up to 32-fold larger volumes than the normal average. Endosomal enlargement contributed to an average 2.5-fold larger total endosomal volume per neuron, implying a marked increase in endocytic activity. Endosomal alterations were evident in most pyramidal neurons in Alzheimer brain, detectable at early stages of the disease but absent in several other neurodegenerative disorders examined. In addition, mature and proenzyme forms of the proteases cathepsin B and cathepsin D, a candidate APP secretase, were identified in most early endosomes in Alzheimer brains but were detectable in only a minor proportion of endosomes in normal brain. Expression of the cation-dependent 46 kDa mannose 6-phosphate receptor was elevated in pyramidal neurons of Alzheimer brains, which could be a possible basis for the altered cathepsin trafficking pattern. Enhanced endocytic activity, coupled with increased trafficking to endosomes of proteases, which may have the ability under pathological conditions to generate A␤, constitutes a potential mechanism by which ␤-amyloidogenesis may become accelerated in sporadic AD and also be subject to influences by ApoE.

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