Alpha- and Beta-secretase Activity As a Function of Age and Beta-amyloid in Down Syndrome and Normal Brain

Overview

Journal Neurobiol Aging

Publisher Elsevier

Specialties Geriatrics
Neurology
Physiology

Date 2006 Aug 15

PMID 16904243

Citations 59

Authors

M Nistor

M Don

M Parekh

F Sarsoza

M Goodus

G E Lopez

C Kawas

J Leverenz

E Doran

I T Lott

M Hill

E Head

Affiliations

Soon will be listed here.

Abstract

Aged individuals with Down syndrome (DS) develop Alzheimer's disease (AD) neuropathology by the age of 40 years. The purpose of the current study was to measure age-associated changes in APP processing in 36 individuals with DS (5 months-69 years) and in 26 controls (5 months-100 years). Alpha-secretase significantly decreased with age in DS, particularly in cases over the age of 40 years and was stable in controls. The levels of C-terminal fragments of APP reflecting alpha-secretase processing (CTF-alpha) decreased with age in both groups. In both groups, there was significant increase in beta-secretase activity with age. CTF-beta remained constant with age in controls suggesting compensatory increases in turnover/clearance mechanisms. In DS, young individuals had the lowest CTF-beta levels that may reflect rapid conversion of beta-amyloid (Abeta) to soluble pools or efficient CTF-beta clearance mechanisms. Treatments to slow or prevent AD in the general population targeting secretase activity may be more efficacious in adults with DS if combined with approaches that enhance Abeta degradation and clearance.

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References

McGowan E, Pickford F, Kim J, Onstead L, Eriksen J, Yu C . Abeta42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron. 2005; 47(2):191-199. PMC: 1373682. DOI: 10.1016/j.neuron.2005.06.030. View

Tanzi R . The synaptic Abeta hypothesis of Alzheimer disease. Nat Neurosci. 2005; 8(8):977-9. DOI: 10.1038/nn0805-977. View

Spires T, Meyer-Luehmann M, Stern E, McLean P, Skoch J, Nguyen P . Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy. J Neurosci. 2005; 25(31):7278-87. PMC: 1820616. DOI: 10.1523/JNEUROSCI.1879-05.2005. View

Rezai-Zadeh K, Shytle D, Sun N, Mori T, Hou H, Jeanniton D . Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice. J Neurosci. 2005; 25(38):8807-14. PMC: 6725500. DOI: 10.1523/JNEUROSCI.1521-05.2005. View

Rovelet-Lecrux A, Hannequin D, Raux G, Le Meur N, Laquerriere A, Vital A . APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet. 2005; 38(1):24-6. DOI: 10.1038/ng1718. View

Mann D, Esiri M . The pattern of acquisition of plaques and tangles in the brains of patients under 50 years of age with Down's syndrome. J Neurol Sci. 1989; 89(2-3):169-79. DOI: 10.1016/0022-510x(89)90019-1. View

Rumble B, Retallack R, Hilbich C, Simms G, Multhaup G, Martins R . Amyloid A4 protein and its precursor in Down's syndrome and Alzheimer's disease. N Engl J Med. 1989; 320(22):1446-52. DOI: 10.1056/NEJM198906013202203. View

Lai F, Williams R . A prospective study of Alzheimer disease in Down syndrome. Arch Neurol. 1989; 46(8):849-53. DOI: 10.1001/archneur.1989.00520440031017. View

Griffin W, Stanley L, Ling C, White L, MacLeod V, Perrot L . Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci U S A. 1989; 86(19):7611-5. PMC: 298116. DOI: 10.1073/pnas.86.19.7611. View

10.

Nordstedt C, Gandy S, Alafuzoff I, Caporaso G, Iverfeldt K, Grebb J . Alzheimer beta/A4 amyloid precursor protein in human brain: aging-associated increases in holoprotein and in a proteolytic fragment. Proc Natl Acad Sci U S A. 1991; 88(20):8910-4. PMC: 52620. DOI: 10.1073/pnas.88.20.8910. View

11.

Vassar R, Bennett B, Kahn S, Mendiaz E, Denis P, Teplow D . Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 1999; 286(5440):735-41. DOI: 10.1126/science.286.5440.735. View

12.

Head E, Azizeh B, Lott I, Tenner A, Cotman C, Cribbs D . Complement association with neurons and beta-amyloid deposition in the brains of aged individuals with Down Syndrome. Neurobiol Dis. 2001; 8(2):252-65. DOI: 10.1006/nbdi.2000.0380. View

13.

Lott I, Head E . Down syndrome and Alzheimer's disease: a link between development and aging. Ment Retard Dev Disabil Res Rev. 2001; 7(3):172-8. DOI: 10.1002/mrdd.1025. View

14.

Nunan J, Shearman M, Checler F, Cappai R, Evin G, Beyreuther K . The C-terminal fragment of the Alzheimer's disease amyloid protein precursor is degraded by a proteasome-dependent mechanism distinct from gamma-secretase. Eur J Biochem. 2001; 268(20):5329-36. DOI: 10.1046/j.0014-2956.2001.02465.x. View

15.

Tyrrell J, Cosgrave M, McCarron M, McPherson J, Calvert J, Kelly A . Dementia in people with Down's syndrome. Int J Geriatr Psychiatry. 2001; 16(12):1168-74. DOI: 10.1002/gps.502. View

16.

Engidawork E, Juranville J, Fountoulakis M, Dierssen M, Lubec G . Selective upregulation of the ubiquitin-proteasome proteolytic pathway proteins, proteasome zeta chain and isopeptidase T in fetal Down syndrome. J Neural Transm Suppl. 2002; (61):117-30. DOI: 10.1007/978-3-7091-6262-0_10. View

17.

Motonaga K, Itoh M, Becker L, Goto Y, Takashima S . Elevated expression of beta-site amyloid precursor protein cleaving enzyme 2 in brains of patients with Down syndrome. Neurosci Lett. 2002; 326(1):64-6. DOI: 10.1016/s0304-3940(02)00287-2. View

18.

Fukumoto H, Cheung B, Hyman B, Irizarry M . Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch Neurol. 2002; 59(9):1381-9. DOI: 10.1001/archneur.59.9.1381. View

19.

Tyler S, Dawbarn D, Wilcock G, Allen S . alpha- and beta-secretase: profound changes in Alzheimer's disease. Biochem Biophys Res Commun. 2002; 299(3):373-6. DOI: 10.1016/s0006-291x(02)02635-9. View

20.

Yang L, Lindholm K, Yan R, Citron M, Xia W, Yang X . Elevated beta-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. Nat Med. 2003; 9(1):3-4. DOI: 10.1038/nm0103-3. View