Citations

Background: Doxorubicin (DOX) is an effective chemotherapy but limited by severe cardiotoxicity. Chemokine receptors CXCR4 and CXCR7 are involved in regulating cardiac survival, inflammation, and fibrosis, yet their specific roles in DOX-induced cardiotoxicity (DICT) remain unclear. Objective: We investigated the cardioprotective effects of TC14012, a dual-target CXCR4 antagonist and CXCR7 agonist, against DICT. Methods: Male C57BL/6J mice received chronic or acute DOX administration with twice-weekly TC14012 treatment. Cardiac function was evaluated by echocardiography. Markers of cardiac fibrosis and inflammation were assessed. RNA-seq analysis was performed to explore associated molecular pathways. Key pathways were validated in cardiac cells and bone marrow-derived mast cells. Results: TC14012 significantly improved cardiac function, indicated by preservation of ejection fraction and fractional shortening, and increased survival rates optimally at 5 mg/kg, which were accompanied with reductions in cardiac collagen deposition and infiltration of macrophages and neutrophils. RNA-seq revealed that TC14012 protecting against DICT was associated with a remarkable stimulation of signals involving in cardiac contraction and energy reserve metabolism processes, particularly glycogen and glucan metabolism that are crucial for meeting the cardiac energy demand in response to DOX induction. These signals could be further enriched into AMPK signalling pathway and validated by enhancement of cardiac AMPK phosphorylation both in vivo and in vitro . Meanwhile, TC14012’s cardioprotective effects were accompanied by a reduction in signals involving in cardiac mast cell activation and degranulation, which could be enriched into Rap1 signalling pathway and validated by TC14012 inhibiting mast cell activation and Rap1-GTP activity in vitro . Importantly, TC14012 did not compromise DOX’s antitumor efficacy in EL-4 lymphoma-bearing mice. Conclusions: TC14012 may prevent DICT by activating CXCR7-AMPK signalling to reprogram cardiomyocyte metabolism and antagonizing CXCR4-Rap1 signalling to blunt mast cell-mediated sentinel effects without compromising the anticancer efficacy DOX.

Background: Doxorubicin (DOX)-induced cardiotoxicity (DICT) has become a serious health burden for cancer survivors. The detrimental effects of CXCR4-mediated excessive inflammation in myocardium and the protective effects of CXCR7 in cardiomyocytes have been demonstrated. Aims: We tested the protective effects against DICT of a dual-targeting compound TC14012, which has specific antagonistic activity against CXCR4 and potent agonistic activity on CXCR7. Methods: Eight-week-old male C57BL/6J mice were injected with DOX for consecutive 5 weeks, during which mice were treated with TC14012 twice a week. One week after the last dose injection, mice were euthanized after heart function examination. Markers of cardiac inflammation and fibrosis were evaluated. Cardiac RNA-seq was performed to explore the underlying molecular pathways. Key findings: TC14012 supplement significantly prevented DOX-induced cardiac systolic dysfunction, reflected by improved ejection fraction and fraction shortening, along with remarkable attenuation of DOX-induced cardiac perivascular and interstitial collagen deposition and neutrophils and macrophage infiltration. RNA-seq revealed that TC14012 prevention of DICT was accompanied with a remarkable stimulation of signals involving in cardiac contraction and energy reserve metabolic process, particularly glycogen and glucan metabolism that are crucial for meeting the cardiac energy demand in response to DOX induction. These signals could be further enriched into AMPK signaling pathway and validated by upregulation of AMPK phosphorylation. Besides, TC14012 prevention of DICT was accompanied with a significant reduction in cardiac mast cell activation and degranulation. These signals could be further enriched into Rap1 signaling pathway, and TC14012 was validated to inhibit Rap1 activity and mast cell activation. Most importantly, TC14012 treatment did not affect the suppressive effects of DOX on tumor growth in a syngeneic EL4 lymphoma-bearing, immunocompetent mouse model. Conclusions: We preliminary conclude that TC14012 prevents DICT by activating cardiac CXCR7 to reprogram cardiomyocyte metabolism and prevent cardiac damage and dysfunction via activating AMPK, and by antagonizing CXCR4 to inhibit cardiac mast cell infiltration and activation via blunting Rap1 activity but does not affect the anti-tumor activity of DOX.

ImportanceIncreased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors.ObjectiveTo estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes.Design, Setting, and ParticipantsThis cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers—the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer’s Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019).Main Outcome and MeasuresThe main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH.ResultsData from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [P = .001]; ADNI: t = 2.7 [P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = −3.1 [P = .002]; ADNI: t = −5.6 [P < .001]; HABS: t = −2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P < .001]; ADNI: t = 9.1 [P < .001]; HABS: t = 5.4 [P < .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40]; ADNI: t = 0.6 [P = .50]; HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P < .001).Conclusions and RelevanceThe findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.

Abstract Introduction Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. Methods We conducted a transethnic genome‐wide association study (GWAS) for late‐onset AD in Stage 1 sample including whites of European Ancestry, African‐Americans, Japanese, and Israeli‐Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Results Genome‐wide significant (GWS) associations in single‐nucleotide polymorphism (SNP)–based tests ( P < 5 × 10 −8 ) were identified for SNPs in PFDN1/HBEGF , USP6NL/ECHDC3 , and BZRAP1‐AS1 and for the interaction of the (apolipoprotein E) APOE ε4 allele with NFIC SNP. We also obtained GWS evidence ( P < 2.7 × 10 −6 ) for gene‐based association in the total sample with a novel locus, TPBG ( P = 1.8 × 10 −6 ). Discussion Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.

A recently identified variant within the fat mass and obesity-associated ( FTO ) gene is carried by 46% of Western Europeans and is associated with an ~1.2 kg higher weight, on average, in adults and an ~1 cm greater waist circumference. With >1 billion overweight and 300 million obese persons worldwide, it is crucial to understand the implications of carrying this very common allele for the health of our aging population. FTO is highly expressed in the brain and elevated body mass index (BMI) is associated with brain atrophy, but it is unknown how the obesity-associated risk allele affects human brain structure. We therefore generated 3D maps of regional brain volume differences in 206 healthy elderly subjects scanned with MRI and genotyped as part of the Alzheimer's Disease Neuroimaging Initiative. We found a pattern of systematic brain volume deficits in carriers of the obesity-associated risk allele versus noncarriers. Relative to structure volumes in the mean template, FTO risk allele carriers versus noncarriers had an average brain volume difference of ~8% in the frontal lobes and 12% in the occipital lobes—these regions also showed significant volume deficits in subjects with higher BMI. These brain differences were not attributable to differences in cholesterol levels, hypertension, or the volume of white matter hyperintensities; which were not detectably higher in FTO risk allele carriers versus noncarriers. These brain maps reveal that a commonly carried susceptibility allele for obesity is associated with structural brain atrophy, with implications for the health of the elderly.