Plcg2M28L Interacts With High Fat/High Sugar Diet to Accelerate Alzheimer\u27s Disease-Relevant Phenotypes in Mice.

Obesity is recognized as a significant risk factor for Alzheimer\u27s disease (AD). Studies have supported the notion that obesity accelerates AD-related pathophysiology in mouse models of AD. The majority of studies, to date, have focused on the use of early-onset AD models. Here, we evaluate the impact of genetic risk factors on late-onset AD (LOAD) in mice fed with a high fat/high sugar diet (HFD). We focused on three mouse models created through the IU/JAX/PITT MODEL-AD Center. These included a combined risk model wit

Prophylactic evaluation of verubecestat on disease- and symptom-modifying effects in 5XFAD mice.

Introduction: Alzheimer\u27s disease (AD) is the most common form of dementia. Beta-secretase (BACE) inhibitors have been proposed as potential therapeutic interventions; however, initiating treatment once disease has significantly progressed has failed to effectively stop or treat disease. Whether BACE inhibition may have efficacy when administered prophylactically in the early stages of AD has been under-investigated. The present studies aimed to evaluate prophylactic treatment of the BACE inhibitor verubecestat in an AD mouse model using the National Institute on Aging (NIA) resources of the Model Organism Development for Late-Onset Alzheimer\u27s Disease (MODEL-AD) Preclinical Testing Core (PTC) Drug Screening Pipeline. Methods: 5XFAD mice were administered verubecestat ad libitum in chow from 3 to 6 months of age, prior to the onset of significant disease pathology. Following treatment (6 months of age), in vivo imaging was conducted with 18F-florbetapir (AV-45/Amyvid) (18F-AV45) and 18-FDG (fluorodeoxyglucose)-PET (positron emission tomography)/MRI (magnetic resonance imaging), brain and plasma amyloid beta (Aβ) were measured, and the clinical and behavioral characteristics of the mice were assessed and correlated with the pharmacokinetic data. Results: Prophylactic verubecestat treatment resulted in dose- and region-dependent attenuations of 18F-AV45 uptake in male and female 5XFAD mice. Plasma Aβ40 and Aβ42 were also dose-dependently attenuated with treatment. Across the dose range evaluated, side effects including coat color changes and motor alterations were reported, in the absence of cognitive improvement or changes in 18F-FDG uptake. Discussion: Prophylactic treatment with verubecestat resulted in attenuated amyloid plaque deposition when treatment was initiated prior to significant pathology in 5XFAD mice. At the same dose range effective at attenuating Aβ levels, verubecestat produced side effects in the absence of improvements in cognitive function. Taken together these data demonstrate the rigorous translational approaches of the MODEL-AD PTC for interrogating potential therapeutics and provide insight into the limitations of verubecestat as a prophylactic intervention for early-stage AD

Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer

We performed a multistage genome-wide association study (GWAS) including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT; per-allele odds ratio [OR] = 0.79; 95% confidence interval [CI] = 0.74–0.84; P = 3.0×10−12), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2; OR = 1.46; 95% CI = 1.30–1.65; P = 1.1×10−10), rs9581943 at 13q12.2 (PDX1; OR = 1.15; 95% CI = 1.10–1.20; P = 2.4×10−9), and rs16986825 at 22q12.1 (ZNRF3; OR = 1.18; 95% CI = 1.12–1.25; P = 1.2×10−8). An independent signal was identified in exon 2 of TERT at the established region 5p15.33 (rs2736098; OR = 0.80; 95% CI = 0.76–0.85; P = 9.8×10−14). We also identified a locus at 8q24.21 (rs1561927; P = 1.3×10−7) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study has identified multiple new susceptibility alleles for pancreatic cancer worthy of follow-up studies

Evaluation of chronic lead effects in the blood brain barrier system by DCE-CT

Background: Lead (Pb) is an environmental factor has been suspected of contributing to the dementia including Alzheimer's disease (AD). Our previous studies have shown that Pb exposure at the subtoxic dose increased brain levels of beta-amyloid (Aβ) and amyloid plaques, a pathological hallmark for AD, in amyloid precursor protein (APP) transgenic mice, and is hypothesized to inhibit Aβ clearance in the blood- cerebrospinal fluid (CSF) barrier. However, it remains unclear how different levels of Pb affect Aβ clearance in the whole blood-brain barrier system. This study was designed to investigate whether chronic exposure of Pb affected the permeability of the blood-brain barrier system by using the Dynamic Contrast-Enhanced Computerized Tomography (DCE-CT) method. Methods: DEC-CT was used to investigate whether chronic exposure of toxic Pb affected the permeability of the real-time blood brain barrier system. Results: Data showed that Pb exposure increased permeability surface area product, and also significantly induced brain perfusion. However, Pb exposure did not alter extracellular volumes or fractional blood volumes of mouse brain. Conclusion: Our data suggest that Pb exposure at subtoxic and toxic levels directly targets the brain vasculature and damages the blood brain barrier system

The 677C \u3e T variant in methylenetetrahydrofolate reductase causes morphological and functional cerebrovascular deficits in mice

Vascular contributions to cognitive impairment and dementia (VCID) particularly Alzheimer\u27s disease and related dementias (ADRDs) are increasing; however, mechanisms driving cerebrovascular decline are poorly understood. Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in the folate and methionine cycles. Variants i

Prophylactic evaluation of verubecestat on disease‐ and symptom‐modifying effects in 5XFAD mice

Abstract Introduction Alzheimer's disease (AD) is the most common form of dementia. Beta‐secretase (BACE) inhibitors have been proposed as potential therapeutic interventions; however, initiating treatment once disease has significantly progressed has failed to effectively stop or treat disease. Whether BACE inhibition may have efficacy when administered prophylactically in the early stages of AD has been under‐investigated. The present studies aimed to evaluate prophylactic treatment of the BACE inhibitor verubecestat in an AD mouse model using the National Institute on Aging (NIA) resources of the Model Organism Development for Late‐Onset Alzheimer's Disease (MODEL‐AD) Preclinical Testing Core (PTC) Drug Screening Pipeline. Methods 5XFAD mice were administered verubecestat ad libitum in chow from 3 to 6 months of age, prior to the onset of significant disease pathology. Following treatment (6 months of age), in vivo imaging was conducted with 18F‐florbetapir (AV‐45/Amyvid) (18F‐AV45) and 18‐FDG (fluorodeoxyglucose)–PET (positron emission tomography)/MRI (magnetic resonance imaging), brain and plasma amyloid beta (Aβ) were measured, and the clinical and behavioral characteristics of the mice were assessed and correlated with the pharmacokinetic data. Results Prophylactic verubecestat treatment resulted in dose‐ and region‐dependent attenuations of 18F‐AV45 uptake in male and female 5XFAD mice. Plasma Aβ40 and Aβ42 were also dose‐dependently attenuated with treatment. Across the dose range evaluated, side effects including coat color changes and motor alterations were reported, in the absence of cognitive improvement or changes in 18F‐FDG uptake. Discussion Prophylactic treatment with verubecestat resulted in attenuated amyloid plaque deposition when treatment was initiated prior to significant pathology in 5XFAD mice. At the same dose range effective at attenuating Aβ levels, verubecestat produced side effects in the absence of improvements in cognitive function. Taken together these data demonstrate the rigorous translational approaches of the MODEL‐AD PTC for interrogating potential therapeutics and provide insight into the limitations of verubecestat as a prophylactic intervention for early‐stage AD