RRC ID 71921
Author Tachida Y, Miura S, Muto Y, Takuwa H, Sahara N, Shindo A, Matsuba Y, Saito T, Taniguchi N, Kawaguchi Y, Tomimoto H, Saido T, Kitazume S.
Title Endothelial expression of human amyloid precursor protein leads to amyloid β in the blood and induces cerebral amyloid angiopathy in knock-in mice.
Journal J Biol Chem
Abstract The deposition of amyloid β (Aβ) in blood vessels of the brain, known as cerebral amyloid angiopathy (CAA), is observed in most patients with Alzheimer's disease (AD). Compared with the pathology of CAA in humans, the pathology in most mouse models of AD is not as evident, making it difficult to examine the contribution of CAA to the pathogenesis of AD. On the basis of biochemical analyses that showed blood levels of soluble amyloid precursor protein (APP) in rats and mice were markedly lower than those measured in human samples, we hypothesized that endothelial APP expression would be markedly lower in rodents and subsequently generated mice that specifically express human WT APP (APP770) in endothelial cells (ECs). The resulting EC-APP770+ mice exhibited increased levels of serum Aβ and soluble APP, indicating that endothelial APP makes a critical contribution to blood Aβ levels. Even though aged EC-APP770+ mice did not exhibit Aβ deposition in the cortical blood vessels, crossing these animals with APP knock-in mice (AppNL-F/NL-F) led to an expanded CAA pathology, as evidenced by increased amounts of amyloid accumulated in the cortical blood vessels. These results highlight an overlooked interplay between neuronal and endothelial APP in brain vascular Aβ deposition. We propose that these EC-APP770+:AppNL-F/NL-F mice may be useful to study the basic molecular mechanisms behind the possible breakdown of the blood-brain barrier upon administration of anti-Aβ antibodies.
Volume 298(6)
Pages 101880
Published 2022-6-1
DOI 10.1016/j.jbc.2022.101880
PII S0021-9258(22)00320-9
PMID 35367207
MeSH Aged Alzheimer Disease* / metabolism Amyloid beta-Peptides* / blood Amyloid beta-Peptides* / genetics Amyloid beta-Peptides* / metabolism Amyloid beta-Protein Precursor* / genetics Amyloid beta-Protein Precursor* / metabolism Animals Brain* / metabolism Brain* / pathology Cerebral Amyloid Angiopathy* / genetics Cerebral Amyloid Angiopathy* / physiopathology Disease Models, Animal Endothelial Cells* / metabolism Endothelial Cells* / pathology Gene Knock-In Techniques Humans Mice Mice, Transgenic Rats
Resource
DNA material pCALNL5 (RDB01862)