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Excess of nicastrin in brain results in heterozygosity having no effect on endogenous APP processing and amyloid peptide levels in vivo.
Neurobiol Dis. 2007 Feb; 25(2):291-6.ND

Abstract

Nicastrin is an integral member of PS-complexes that perform gamma-secretase cleavage of numerous type I membrane proteins including amyloid precursor protein that underlies Alzheimer's disease; thus, diminishing gamma-secretase activity by reducing levels of functional PS-complexes is suggested as a possible preventative/therapeutic avenue for the disease. One means of reducing PS-complex activity entails decreasing the levels of one or more of its components, such as nicastrin, which is fundamental to its assembly. Two previous studies detailing the effects of decreased nicastrin on gamma-secretase cleavage of APP in nicastrin heterozygous mouse fibroblast, which express relatively low levels of endogenous nicastrin compared to neurons, were contradictory. One report documented a 50% reduction in gamma-secretase cleavage of APP while the second showed markedly higher levels of this activity. Here we report that brains of heterozygous nicastrin mice show no difference in levels of APP gamma-secretase cleavage, APP C-terminal fragments or beta-amyloid peptides, compared to wild-type. This result is explained by the levels of nicastrin protein and functional presenilin complexes being similar between the heterozygous and wild-type brains, though nicastrin mRNA levels were diminished appropriately in the former. These in vivo results indicate that nicastrin mRNA and its immature protein are likely in overabundance in neurons and not limiting for assembly of PS-complexes, and that a 50% reduction of its mRNA or protein production would not affect APP processing, in contrast to fibroblast. Thus, partial reduction (maintaining a level above 50% of normal) of brain nicastrin would likely not be efficacious in reducing functional PS-complexes and gamma-secretase activity as a therapeutic strategy for Alzheimer's disease.

Authors+Show Affiliations

Department of Biochemistry, University of Western Ontario, London, Ontario, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17071095

Citation

Brijbassi, Sonya, et al. "Excess of Nicastrin in Brain Results in Heterozygosity Having No Effect On Endogenous APP Processing and Amyloid Peptide Levels in Vivo." Neurobiology of Disease, vol. 25, no. 2, 2007, pp. 291-6.
Brijbassi S, Amtul Z, Newbigging S, et al. Excess of nicastrin in brain results in heterozygosity having no effect on endogenous APP processing and amyloid peptide levels in vivo. Neurobiol Dis. 2007;25(2):291-6.
Brijbassi, S., Amtul, Z., Newbigging, S., Westaway, D., St George-Hyslop, P., & Rozmahel, R. F. (2007). Excess of nicastrin in brain results in heterozygosity having no effect on endogenous APP processing and amyloid peptide levels in vivo. Neurobiology of Disease, 25(2), 291-6.
Brijbassi S, et al. Excess of Nicastrin in Brain Results in Heterozygosity Having No Effect On Endogenous APP Processing and Amyloid Peptide Levels in Vivo. Neurobiol Dis. 2007;25(2):291-6. PubMed PMID: 17071095.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Excess of nicastrin in brain results in heterozygosity having no effect on endogenous APP processing and amyloid peptide levels in vivo. AU - Brijbassi,Sonya, AU - Amtul,Zareen, AU - Newbigging,Susan, AU - Westaway,David, AU - St George-Hyslop,Peter, AU - Rozmahel,Richard F, Y1 - 2006/10/27/ PY - 2006/07/17/received PY - 2006/09/09/revised PY - 2006/09/19/accepted PY - 2006/10/31/pubmed PY - 2007/4/12/medline PY - 2006/10/31/entrez SP - 291 EP - 6 JF - Neurobiology of disease JO - Neurobiol Dis VL - 25 IS - 2 N2 - Nicastrin is an integral member of PS-complexes that perform gamma-secretase cleavage of numerous type I membrane proteins including amyloid precursor protein that underlies Alzheimer's disease; thus, diminishing gamma-secretase activity by reducing levels of functional PS-complexes is suggested as a possible preventative/therapeutic avenue for the disease. One means of reducing PS-complex activity entails decreasing the levels of one or more of its components, such as nicastrin, which is fundamental to its assembly. Two previous studies detailing the effects of decreased nicastrin on gamma-secretase cleavage of APP in nicastrin heterozygous mouse fibroblast, which express relatively low levels of endogenous nicastrin compared to neurons, were contradictory. One report documented a 50% reduction in gamma-secretase cleavage of APP while the second showed markedly higher levels of this activity. Here we report that brains of heterozygous nicastrin mice show no difference in levels of APP gamma-secretase cleavage, APP C-terminal fragments or beta-amyloid peptides, compared to wild-type. This result is explained by the levels of nicastrin protein and functional presenilin complexes being similar between the heterozygous and wild-type brains, though nicastrin mRNA levels were diminished appropriately in the former. These in vivo results indicate that nicastrin mRNA and its immature protein are likely in overabundance in neurons and not limiting for assembly of PS-complexes, and that a 50% reduction of its mRNA or protein production would not affect APP processing, in contrast to fibroblast. Thus, partial reduction (maintaining a level above 50% of normal) of brain nicastrin would likely not be efficacious in reducing functional PS-complexes and gamma-secretase activity as a therapeutic strategy for Alzheimer's disease. SN - 0969-9961 UR - https://www.unboundmedicine.com/medline/citation/17071095/Excess_of_nicastrin_in_brain_results_in_heterozygosity_having_no_effect_on_endogenous_APP_processing_and_amyloid_peptide_levels_in_vivo_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0969-9961(06)00240-3 DB - PRIME DP - Unbound Medicine ER -