Background: Cerebral amyloid angiopathy (CAA) co-occurs with neurodegeneration in Alzheimer's disease (AD). CAA is absent in many AD mouse models, rendering CAA difficult to study. Previous work has shown wild-derived WSB/EiJ (WSB) mice over-expressing APP/PS1 had increased CAA, and thus may be useful in investigating CAA-causing mechanisms. Here, genetic backgrounds with CAA susceptibility (WSB.APP/PS1) and resilience (B6.APP/PS1) are leveraged to map CAA-susceptibility loci. Furthermore, blood brain barrier (BBB) compromise has been hypothesized to impair amyloid clearance and promote vascular deposition. Endothelial TIE2 deactivation was shown to weaken BBB integrity in other models, and therefore may drive CAA. TIE2 activation (pTIE2) is inhibited by endogenous antagonists ANGPT2 and PTPRB, which can be manipulated to bolster pTIE2. Here, the efficacy of pTIE2 elevation in preventing CAA in AD is investigated.
Methods: To determine the onset and therapeutic window of CAA, WSB.APP/PS1 mice (n≥3/sex) were aged to 4, 6, 8, 14, and 18M. CAA was assessed using immunohistochemistry (X34+ plaques within CD31+ vessels). To map CAA-susceptibility loci, B6.APP/PS1 and WSB mice were crossed, generating BXW.APP/PS1 (F1) offspring. To determine haplosufficiency of these alleles, CAA was evaluated in BXW.APP/PS1 mice (n = 6/sex). F1 mice were intercrossed to generate heterogeneous F2 progeny (n = 50/sex), which were assessed for CAA. To elevate pTIE2 in models of CAA/AD, Angpt2 heterozygous (Angpt2) and Ptprb loss-of-function (Ptprb) alleles were bred to generate CAA-susceptible mice with TIE2 modulation. Western blot analysis is employed to confirm elevated pTIE2, and CAA amelioration will be evaluated.
Results: WSB.APP/PS1 mice developed significant CAA by 8M. CAA was significantly more advanced in BXW.APP/PS1 compared to founder strains at 8M, and F2 mice had varying CAA severity. Late-onset AD mice (LOAD2, JAX #033867) with Ptprb exhibited pTIE2 elevation at 12M.
Conclusions: Robust BXW.APP/PS1 CAA suggests heterozygous loci promote CAA. F2 CAA variability suggests CAA-susceptibility loci are likely mappable. F2 SNP analysis and R/qtl2 software is being employed to identify candidate loci corresponding with CAA. Furthermore, BXW.APP/PS1 is a novel CAA model to study the therapeutic potential of pTIE2 enhancement. To this end, BXW.Angpt2APP/PS1 and BXW.PtprbAPP/PS1 mice are aging and will be evaluated for pTIE2 elevation and CAA attenuation.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1002/alz.091446 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Association of vitamin D receptor gene polymorphisms, metabolic features and susceptibility to polycystic ovary syndrome: a preliminary study.
Reprod Biomed Online
September 2024
UMF Iuliu Haţieganu, Cluj-Napoca, Romania.
Research Question: Are the combined genotypes and haplotypes of vitamin D receptor (VDR) gene polymorphisms (FokI, ApaI and TaqI) associated with susceptibility to polycystic ovary syndrome (PCOS) and metabolic features of the disease?
Design: This case-control study included 46 women with PCOS and 48 controls. Genotypes of the VDR gene were determined using the polymerase chain reaction-restriction fragment length polymorphism method. Waist circumference, and parameters of lipid and glucose metabolism were evaluated in all women.
Basic Science and Pathogenesis.
Alzheimers Dement
December 2024
Eli Lilly and Company, Indianapolis, IN, USA.
Background: Anti-amyloid-β (Aβ) immunotherapy trials have shown amyloid-related imaging abnormalities (ARIA) as the most common and serious adverse events linked to pathological changes in cerebral vasculature. Nevertheless, the mechanisms underlying how amyloid immunotherapy triggers vascular damage, increases vascular permeability, and results in microhemorrhages remains unclear. Notably, activation of perivascular macrophages and infiltration of peripheral immune cells have been implicated in regulating cerebrovascular damage.
View Article and Find Full Text PDFNomogram model based on serum chitotriosidase activity to predict coronary artery aneurysm in Kawasaki disease.
Coron Artery Dis
January 2025
Department of Pediatrics, Pidu Maternal and Child Care Hospital.
Objective: Kawasaki disease (KD) is a common children's disease with unknown etiology, which easily involves coronary artery and causes serious cardiovascular sequelae. The purpose was to investigate the relationship between chitotriosidase activity and coronary artery aneurysm (CAA) and develop and validate a nomogram to predict CAA in KD patients.
Methods: A total of 338 KD patients were included in this study.
Basic Science and Pathogenesis.
Alzheimers Dement
December 2024
The Jackson Laboratory, Bar Harbor, ME, USA.
Background: Cerebral amyloid angiopathy (CAA) co-occurs with neurodegeneration in Alzheimer's disease (AD). CAA is absent in many AD mouse models, rendering CAA difficult to study. Previous work has shown wild-derived WSB/EiJ (WSB) mice over-expressing APP/PS1 had increased CAA, and thus may be useful in investigating CAA-causing mechanisms.
View Article and Find Full Text PDFBasic Science and Pathogenesis.
Alzheimers Dement
December 2024
The University of Sydney, Sydney, NSW, Australia.
Background: SMOC1 has recently emerged as one of the most significant and consistent new biomarkers of early Alzheimer's disease (AD). SMOC1 is one of the earliest changing proteins in AD, with SMOC1 cerebrospinal fluid levels increasing 29 years before symptom onset in autosomal dominant AD. Despite this clear association with disease, very little is known about the role of SMOC1 in AD or its function in the brain.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!