Peripheral reduction of β-amyloid is sufficient to reduce brain β-amyloid: implications for Alzheimer's disease

J Gregor Sutcliffe; Peter B Hedlund; Elizabeth A Thomas; Floyd E Bloom; Brian S Hilbush

doi:10.1002/jnr.22603

Peripheral reduction of β-amyloid is sufficient to reduce brain β-amyloid: implications for Alzheimer's disease

J Neurosci Res. 2011 Jun;89(6):808-14. doi: 10.1002/jnr.22603. Epub 2011 Mar 3.

Authors

J Gregor Sutcliffe¹, Peter B Hedlund, Elizabeth A Thomas, Floyd E Bloom, Brian S Hilbush

Affiliation

¹ Department of Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA. gregorsutcliffe@aol.com

PMID: 21374699
DOI: 10.1002/jnr.22603

Abstract

Three loci that modify β-amyloid (Aβ) accumulation and deposition in the brains of a mouse model of Alzheimer's disease have been previously described. One encompasses the Psen2 gene encoding presenilin 2, a component of the γ-secretase activity responsible for generating Aβ by proteolysis. We show that the activity of mouse Psen2, as measured by levels of mRNA accumulation, unexpectedly is heritable in the liver but not the brain, suggesting liver as the origin of brain Aβ deposits. Administration of STI571, a cancer therapeutic that does not cross the blood-brain barrier, reduced accumulation of Aβ in both the blood and the brain, confirming brain Aβ's peripheral origin and suggesting that STI571 and related compounds might have therapeutic/prophylactic value in human Alzheimer's disease. The genes Cib1 and Zfhx1b reside within the other modifier loci and also exhibit heritable expression in the liver, suggesting that they too contribute to Aβ accumulation.

MeSH terms

Alzheimer Disease / blood*
Alzheimer Disease / drug therapy
Alzheimer Disease / pathology*
Amyloid beta-Peptides
Animals
Benzamides
Brain / drug effects
Brain / metabolism*
Brain / pathology
Calcium-Binding Proteins / genetics
Calcium-Binding Proteins / metabolism
Chromosomes, Human, Pair 2 / genetics
Chromosomes, Human, Pair 7 / genetics
Disease Models, Animal
Enzyme-Linked Immunosorbent Assay / methods
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism
Humans
Imatinib Mesylate
Mice
Mice, Inbred C57BL
Mice, Inbred DBA
Mice, Transgenic
Piperazines / therapeutic use
Presenilin-2 / genetics
Protein Kinase Inhibitors / therapeutic use
Pyrimidines / therapeutic use
Quantitative Trait Loci
RNA, Messenger / metabolism
Repressor Proteins / genetics
Repressor Proteins / metabolism
Zinc Finger E-box Binding Homeobox 2

Substances

Amyloid beta-Peptides
Benzamides
Calcium-Binding Proteins
Cib1 protein, mouse
Homeodomain Proteins
Piperazines
Presenilin-2
Protein Kinase Inhibitors
Pyrimidines
RNA, Messenger
Repressor Proteins
ZEB2 protein, mouse
Zinc Finger E-box Binding Homeobox 2
Imatinib Mesylate