Alzheimer's-related Endosome Dysfunction in Down Syndrome is Abeta-independent but Requires APP and is Reversed by BACE-1 Inhibition

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2010 Jan 19

PMID 20080541

Citations 181

Authors

Ying Jiang

Kerry A Mullaney

Corrinne M Peterhoff

Shaoli Che

Stephen D Schmidt

Anne Boyer-Boiteau

Stephen D Ginsberg

Anne M Cataldo

Paul M Mathews

Ralph A Nixon

Affiliations

Soon will be listed here.

Abstract

An additional copy of the beta-amyloid precursor protein (APP) gene causes early-onset Alzheimer's disease (AD) in trisomy 21 (DS). Endosome dysfunction develops very early in DS and AD and has been implicated in the mechanism of neurodegeneration. Here, we show that morphological and functional endocytic abnormalities in fibroblasts from individuals with DS are reversed by lowering the expression of APP or beta-APP-cleaving enzyme 1 (BACE-1) using short hairpin RNA constructs. By contrast, endosomal pathology can be induced in normal disomic (2N) fibroblasts by overexpressing APP or the C-terminal APP fragment generated by BACE-1 (betaCTF), all of which elevate the levels of betaCTFs. Expression of a mutant form of APP that cannot undergo beta-cleavage had no effect on endosomes. Pharmacological inhibition of APP gamma-secretase, which markedly reduced Abeta production but raised betaCTF levels, also induced AD-like endosome dysfunction in 2N fibroblasts and worsened this pathology in DS fibroblasts. These findings strongly implicate APP and the betaCTF of APP, and exclude Abeta and the alphaCTF, as the cause of endocytic pathway dysfunction in DS and AD, underscoring the potential multifaceted value of BACE-1 inhibition in AD therapeutics.

Citing Articles

Genetic and pharmacologic enhancement of SUMO2 conjugation prevents and reverses cognitive impairment and synaptotoxicity in a preclinical model of Alzheimer's disease.

Fioriti L, Wijesekara N, Argyrousi E, Matsuzaki S, Takamura H, Satoh K Alzheimers Dement. 2025; 21(3):e70030.

PMID: 40047257 PMC: 11883658. DOI: 10.1002/alz.70030.

Comparison of the amyloid plaque proteome in Down syndrome, early-onset Alzheimer's disease, and late-onset Alzheimer's disease.

Marta-Ariza M, Leitner D, Kanshin E, Suazo J, Giusti Pedrosa A, Thierry M Acta Neuropathol. 2025; 149(1):9.

PMID: 39825890 PMC: 11742868. DOI: 10.1007/s00401-025-02844-z.

Down syndrome frontal cortex layer III and layer V pyramidal neurons exhibit lamina specific degeneration in aged individuals.

Alldred M, Ibrahim K, Pidikiti H, Chiosis G, Mufson E, Stutzmann G Acta Neuropathol Commun. 2024; 12(1):182.

PMID: 39605035 PMC: 11603868. DOI: 10.1186/s40478-024-01891-z.

Maternal choline supplementation rescues early endosome pathology in basal forebrain cholinergic neurons in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease.

Gautier M, Kelley C, Lee S, Mufson E, Ginsberg S Neurobiol Aging. 2024; 144:30-42.

PMID: 39265450 PMC: 11490376. DOI: 10.1016/j.neurobiolaging.2024.09.002.

Autophagy-lysosomal-associated neuronal death in neurodegenerative disease.

Nixon R Acta Neuropathol. 2024; 148(1):42.

PMID: 39259382 PMC: 11418399. DOI: 10.1007/s00401-024-02799-7.

References

Cataldo A, Petanceska S, Peterhoff C, Terio N, Epstein C, Villar A . App gene dosage modulates endosomal abnormalities of Alzheimer's disease in a segmental trisomy 16 mouse model of down syndrome. J Neurosci. 2003; 23(17):6788-92. PMC: 6740714. View

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

Wolfe M, Esler W, Das C . Continuing strategies for inhibiting Alzheimer's gamma-secretase. J Mol Neurosci. 2002; 19(1-2):83-7. DOI: 10.1007/s12031-002-0015-5. View

Jin L, Shie F, Maezawa I, Vincent I, Bird T . Intracellular accumulation of amyloidogenic fragments of amyloid-beta precursor protein in neurons with Niemann-Pick type C defects is associated with endosomal abnormalities. Am J Pathol. 2004; 164(3):975-85. PMC: 1614713. DOI: 10.1016/s0002-9440(10)63185-9. View

Hardy J, Selkoe D . The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002; 297(5580):353-6. DOI: 10.1126/science.1072994. View

Nixon R . Autophagy, amyloidogenesis and Alzheimer disease. J Cell Sci. 2007; 120(Pt 23):4081-91. DOI: 10.1242/jcs.019265. View

Geller L, Potter H . Chromosome missegregation and trisomy 21 mosaicism in Alzheimer's disease. Neurobiol Dis. 1999; 6(3):167-79. DOI: 10.1006/nbdi.1999.0236. View

Holtzman D, Santucci D, Kilbridge J, Fontana D, Daniels S, Johnson R . Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome. Proc Natl Acad Sci U S A. 1996; 93(23):13333-8. PMC: 24093. DOI: 10.1073/pnas.93.23.13333. View

Margallo-Lana M, Morris C, Gibson A, Tan A, Kay D, Tyrer S . Influence of the amyloid precursor protein locus on dementia in Down syndrome. Neurology. 2004; 62(11):1996-8. DOI: 10.1212/01.wnl.0000129275.13169.be. View

10.

Ginsberg S, Che S, Wuu J, Counts S, Mufson E . Down regulation of trk but not p75NTR gene expression in single cholinergic basal forebrain neurons mark the progression of Alzheimer's disease. J Neurochem. 2006; 97(2):475-87. DOI: 10.1111/j.1471-4159.2006.03764.x. View

11.

Brummelkamp T, Bernards R, Agami R . A system for stable expression of short interfering RNAs in mammalian cells. Science. 2002; 296(5567):550-3. DOI: 10.1126/science.1068999. View

12.

Cataldo A, Peterhoff C, Troncoso J, Gomez-Isla T, Hyman B, Nixon R . Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer's disease and Down syndrome: differential effects of APOE genotype and presenilin mutations. Am J Pathol. 2000; 157(1):277-86. PMC: 1850219. DOI: 10.1016/s0002-9440(10)64538-5. View

13.

Kao S, Krichevsky A, Kosik K, Tsai L . BACE1 suppression by RNA interference in primary cortical neurons. J Biol Chem. 2003; 279(3):1942-9. DOI: 10.1074/jbc.M309219200. View

14.

Singer O, Marr R, Rockenstein E, Crews L, Coufal N, Gage F . Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model. Nat Neurosci. 2005; 8(10):1343-9. DOI: 10.1038/nn1531. View

15.

Mathews P, Jiang Y, Schmidt S, Grbovic O, Mercken M, Nixon R . Calpain activity regulates the cell surface distribution of amyloid precursor protein. Inhibition of calpains enhances endosomal generation of beta-cleaved C-terminal APP fragments. J Biol Chem. 2002; 277(39):36415-24. DOI: 10.1074/jbc.M205208200. View

16.

Choi J, Berger J, Mazzella M, Morales-Corraliza J, Cataldo A, Nixon R . Age-dependent dysregulation of brain amyloid precursor protein in the Ts65Dn Down syndrome mouse model. J Neurochem. 2009; 110(6):1818-27. PMC: 2744432. DOI: 10.1111/j.1471-4159.2009.06277.x. View

17.

Rajendran L, Schneider A, Schlechtingen G, Weidlich S, Ries J, Braxmeier T . Efficient inhibition of the Alzheimer's disease beta-secretase by membrane targeting. Science. 2008; 320(5875):520-3. DOI: 10.1126/science.1156609. View

18.

Kaether C, Schmitt S, Willem M, Haass C . Amyloid precursor protein and Notch intracellular domains are generated after transport of their precursors to the cell surface. Traffic. 2006; 7(4):408-15. DOI: 10.1111/j.1600-0854.2006.00396.x. View

19.

Nistor M, Don M, Parekh M, Sarsoza F, Goodus M, Lopez G . Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain. Neurobiol Aging. 2006; 28(10):1493-506. PMC: 3375834. DOI: 10.1016/j.neurobiolaging.2006.06.023. View

20.

Arbel M, Yacoby I, Solomon B . Inhibition of amyloid precursor protein processing by beta-secretase through site-directed antibodies. Proc Natl Acad Sci U S A. 2005; 102(21):7718-23. PMC: 1140443. DOI: 10.1073/pnas.0502427102. View