| 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
|
| PMC |
PMC9144051
|
| 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
|
| IF |
4.238
|
| Resource |
| DNA material |
pCALNL5 (RDB01862) |
