Efficient Inhibition of the Alzheimer's Disease β-Secretase by Membrane Targeting

Rajendran, Lawrence; Schneider, Anja; Schlechtingen, Georg; Weidlich, Sebastian; Ries, Jonas; Braxmeier, Tobias; Schwille, Petra; Schulz, Jörg B.; Schroeder, Cornelia; Simons, Mikael; Jennings, Gary; Knölker, Hans‐Joachim; Simons, Kai

doi:10.1126/science.1156609

Cited by 245 publications

(211 citation statements)

References 26 publications

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“…It is further conceivable that reduction in Reelinsignaling promotes APP endocytosis because of reduced binding of the central Reelin domain to the N terminus of APP (Hoe et al, 2009). This scenario fits with previous data showing preferential APP ␤-secretase cleavage in endocytic vesicles (Rajendran et al, 2006(Rajendran et al, , 2008, in line with the reported endosomal localization and pH optimum of ␤-secretase activity (Vassar et al, 1999).…”

Section: Discussionsupporting

confidence: 79%

Reduced Reelin Expression Accelerates Amyloid- Plaque Formation and Tau Pathology in Transgenic Alzheimer's Disease Mice

Kocherhans¹,

Madhusudan²,

Doehner³

et al. 2010

Journal of Neuroscience

108

101

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In addition to the fundamental role of the extracellular glycoprotein Reelin in neuronal development and adult synaptic plasticity, alterations in Reelin-mediated signaling have been suggested to contribute to neuronal dysfunction associated with Alzheimer's disease (AD). In vitro data revealed a biochemical link between Reelin-mediated signaling, Tau phosphorylation, and amyloid precursor protein (APP) processing. To directly address the role of Reelin in amyloid-␤ plaque and Tau pathology in vivo, we crossed heterozygous Reelin knock-out mice (reeler) with transgenic AD mice to investigate the temporal and spatial AD-like neuropathology. We demonstrate that a reduction in Reelin expression results in enhanced amyloidogenic APP processing, as indicated by the precocious production of amyloid-␤ peptides, the significant increase in number and size of amyloid-␤ plaques, as well as age-related aggravation of plaque pathology in double mutant compared with single AD mutant mice of both sexes. Numerous amyloid-␤ plaques accumulate in the hippocampal formation and neocortex of double mutants, precisely in layers with strongest Reelin expression and highest accumulation of Reelin plaques in aged wild-type mice. Moreover, concentric accumulations of phosphorylated Tau-positive neurons around amyloid-␤ plaques were evident in 15-month-old double versus single mutant mice. Silver stainings indicated the presence of neurofibrillary tangles, selectively associated with amyloid-␤ plaques and dystrophic neurites in the entorhinal cortex and hippocampus. Our findings suggest that age-related Reelin aggregation and concomitant reduction in Reelin-mediated signaling play a proximal role in synaptic dysfunction associated with amyloid-␤ deposition, sufficient to enhance Tau phosphorylation and tangle formation in the hippocampal formation in aged Reelin-deficient transgenic AD mice.

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Section: Discussionsupporting

confidence: 79%

Reduced Reelin Expression Accelerates Amyloid- Plaque Formation and Tau Pathology in Transgenic Alzheimer's Disease Mice

Kocherhans¹,

Madhusudan²,

Doehner³

et al. 2010

Journal of Neuroscience

108

101

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“…The same quasiirreversible binding is achieved with a single cholesteryl moiety (47). The use of cholesterol for membrane targeting of a peptide has just been described to increase the potency of a transitionstate ␤-secretase inhibitor (48).…”

mentioning

confidence: 77%

“…Notably, in the only other reported example of cholesterol tethering to a peptide, the same absolute need for C-terminal versus N-terminal linkage of cholesterol was observed, and palmitoyl derivatization was inferior to cholesterol in promoting biological activity (48).…”

mentioning

confidence: 99%

Addition of a cholesterol group to an HIV-1 peptide fusion inhibitor dramatically increases its antiviral potency

Ingallinella

Bianchi

Ladwa

et al. 2009

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

185

247

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Peptides derived from the heptad repeat 2 (HR2) region of the HIV fusogenic protein gp41 are potent inhibitors of viral infection, and one of them, enfuvirtide, is used for the treatment of therapyexperienced AIDS patients. The mechanism of action of these peptides is binding to a critical intermediate along the virus-cell fusion pathway, and accordingly, increasing the affinity for the intermediate yields more potent inhibitors. We took a different approach, namely to increase the potency of the HR2 peptide inhibitor C34 by targeting it to the cell compartment where fusion occurs, and we show here that a simple, yet powerful way to accomplish this is attachment of a cholesterol group. C34 derivatized with cholesterol (C34-Chol) shows dramatically increased antiviral potency on a panel of primary isolates, with IC 90 values 15-to 300-fold lower than enfuvirtide and the second-generation inhibitor T1249, making C34-Chol the most potent HIV fusion inhibitor to date. Consistent with its anticipated mechanism of action, the antiviral activity of C34-Chol is unusually persistent: washing target cells after incubation with C34-Chol, but before triggering fusion, increases IC 50 only 7-fold, relative to a 400-fold increase observed for C34. Moreover, derivatization with cholesterol extends the half-life of the peptide in vivo. In the mouse, s.c. administration of 3.5 mg/kg C34-Chol yields a plasma concentration 24 h after injection >300-fold higher than the measured IC 90 values. Because the fusion machinery targeted by C34-Chol is similar in several other enveloped viruses, we believe that these findings may be of general utility. antiretroviral drug ͉ enveloped viruses ͉ lipid rafts ͉ peptide therapeutic

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“…To ensure their accumulation within endosomes, a membrane-anchored BACE1 transition-state inhibitor was linked to a sterol moiety. Because of its selective accumulation within endosomes, the membrane-bound inhibitor reduced BACE1 activity much more efficiently than a nonmembrane anchored version (Rajendran et al 2008). However, BACE1 activity is not exclusively restricted to endosomes.…”

Section: Trafficking and Proteolytic Processing Of Appmentioning

confidence: 99%

Trafficking and Proteolytic Processing of APP

Haass¹,

Kaether²,

Wang³

et al. 2012

Cold Spring Harbor Perspectives in Medicine

867

888

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Accumulations of insoluble deposits of amyloid b-peptide are major pathological hallmarks of Alzheimer disease. Amyloid b-peptide is derived by sequential proteolytic processing from a large type I trans-membrane protein, the b-amyloid precursor protein. The proteolytic enzymes involved in its processing are named secretases. b-and g-secretase liberate by sequential cleavage the neurotoxic amyloid b-peptide, whereas a-secretase prevents its generation by cleaving within the middle of the amyloid domain. In this chapter we describe the cell biological and biochemical characteristics of the three secretase activities involved in the proteolytic processing of the precursor protein. In addition we outline how the precursor protein maturates and traffics through the secretory pathway to reach the subcellular locations where the individual secretases are preferentially active. Furthermore, we illuminate how neuronal activity and mutations which cause familial Alzheimer disease affect amyloid b-peptide generation and therefore disease onset and progression.

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Efficient Inhibition of the Alzheimer's Disease β-Secretase by Membrane Targeting

Cited by 245 publications

References 26 publications

Reduced Reelin Expression Accelerates Amyloid- Plaque Formation and Tau Pathology in Transgenic Alzheimer's Disease Mice

Reduced Reelin Expression Accelerates Amyloid- Plaque Formation and Tau Pathology in Transgenic Alzheimer's Disease Mice

Addition of a cholesterol group to an HIV-1 peptide fusion inhibitor dramatically increases its antiviral potency

Trafficking and Proteolytic Processing of APP

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