Radiolabeled MCP-1 can detect abnormally increased numbers of perivascular mononuclear cells in native and grafted hearts in prediabetic rats. MCP-1 may be useful in the screening of diabetic children for early atherosclerotic disease.

Alzheimer’s disease (AD), the leading cause of dementia, affects millions of people worldwide. With no disease-modifying medication currently available, the human toll and economic costs are rising rapidly. Under current standards, a patient is diagnosed with AD when both cognitive decline and pathology (amyloid plaques and neurofibrillary tangles) are present. Remarkably, some individuals who have AD pathology remain cognitively normal. Uncovering factors that lead to “cognitive resilience” to AD is a promising path to create new targets for therapies. However, technical challenges discovering novel human resilience factors limit testing, validation, and nomination of novel drugs for AD. In this study, we use single-nuclear transcriptional profiles of postmortem cortex from human individuals with high AD pathology who were either cognitively normal (resilient) or cognitively impaired (susceptible) at time of death, as well as mouse strains that parallel these differences in cognition with high amyloid. Our cross-species discovery approach highlights a novel role for excitatory layer 4/5 cortical neurons in promoting cognitive resilience to AD, and nominates several resilience genes that include ATP1A1, GABRB1, PTK2, and ROCK2. Nominated resilience genes were tested for replication in orthogonal data sets and confirmed to be correlated with cognitive resilience. Additionally, we identified several potential mechanisms of resilience, including regulation of membrane potential, axonal and dendritic growth, and general increase of protein cycle, potentially of membrane proteins. Because our discovery of resilience-associated genes in layer 4/5 cortical neurons originates from an integrated human and mouse transcriptomic space from susceptible and resilient individuals, we are positioned to test causality and perform mechanistic, validation, and pre-clinical studies in our human-relevant AD-BXD mouse panel.

BackgroundAlzheimer’s disease (AD), the leading cause of dementia, affects millions of people worldwide. With no disease‐modifying medication currently available, the human toll and economic costs are rising rapidly. Under current standards, a patient is diagnosed with AD when both cognitive decline and pathology (amyloid plaques and neurofibrillary tangles) are present. Remarkably, some individuals who have AD pathology remain cognitively normal. Uncovering factors that lead to “cognitive resilience” to AD is a promising path to create new targets for therapies. However, technical challenges discovering novel human resilience factors limit testing, validation, and nomination of novel drugs for AD.MethodIn this study, we use single‐nuclear transcriptional profiles of postmortem cortex from human individuals with high AD pathology who were either cognitively normal (resilient) or cognitively impaired (susceptible) at time of death, as well as mouse strains that parallel these differences in cognition with high amyloid.ResultOur cross‐species discovery approach highlights a novel role for excitatory layer 4/5 cortical neurons in promoting cognitive resilience to AD, and nominates several resilience genes that include ATP1A1, GABRB1, PTK2, and ROCK2. Nominated resilience genes were tested for replication in orthogonal data sets and confirmed to be correlated with cognitive resilience. Additionally, we identified several potential mechanisms of resilience, including regulation of membrane potential, axonal and dendritic growth, and general increase of protein cycle, potentially of membrane proteins.ConclusionBecause our discovery of resilience‐associated genes in layer 4/5 cortical neurons originates from an integrated human and mouse transcriptomic space from susceptible and resilient individuals, we are positioned to test causality and perform mechanistic, validation, and pre‐clinical studies in our human‐relevant AD‐BXD mouse panel.

Recent studies, both clinical and experimental, indicate that many neurodegenerative disorders including Alzheimer’s disease (AD) often display coexisting metabolic dysfunctions, which may exacerbate neurological symptoms. The hypothalamus is a brain region highly involved in maintaining metabolic and other homeostatic processes and is known to be involved in the etiology of AD, although the role of hypothalamic dysfunction in the onset, progression, and severity of AD is poorly understood. In this study, we demonstrate that our new model of genetic diversity in AD, the AD-BXDs, exhibits non-cognitive symptoms consistent with hypothalamic dysfunction and examined hypothalamic bulk RNA sequencing data in the AD-BXD panel to investigate how the AD transgene impacts gene expression profiles in the hypothalamus. Mostly notably, we identified strong neuroinflammatory signatures from the hypothalamus in the AD-BXDs as early as six months of age. A functionally unknown WGCNA module showed correlation to female body weight and contextual fear acquisition. Eigengene expression of microglial/macrophagic modules and their hub gene expressions were correlated to cognitive phenotypes. From these analyses, we nominated Plek and Laptm5 as new targets to attenuate neuroinflammation in AD.

BackgroundGenetic background is known to significantly affect the behavioral and molecular phenotypes in mice and has been well documented over many disease areas including Alzheimer’s disease (AD). However, how different background strains and their interaction with environmental factors such as high fat diet (HFD) could have an impact on metabolic phenotypes in AD not known.MethodTo determine how genetic background, diet, sex and age contributes to the metabolic profile in AD, 2.5 months old male and females 5xFAD mice on C57BL/6J (B6) and B6D2 background were fed either normal chow diet, or 45% high‐fat diet till 6 or14 months of age and compared to their age matched non‐transgenic littermate controls. Blood plasma samples were collected and a four‐mode discovery metabolomics approach on a Q‐Exactive Orbitrap coupled to an ultra‐high‐performance liquid chromatography (UHPLC) system was used to analyze metabolic changes.ResultFollowing the quality assessment of spectral data, the dataset contained a total of 21,746 features across C18 and HILIC columns run with negative and positive ionization. After further filtering for named metabolites, removing duplicates, and a Fragment Ion Search (FISh) Score > 10, a total of 3,199 unique metabolites with high confidence MS2 fragmentation remained. Using linear regression analysis on these unique metabolites, we found that diet has a substantial impact (of all the factors tested including diet, sex, age, background strain, genotype) on plasma metabolites in both the strains with and without 5XFAD genotype, both in positive and negative mode of C18 and HILIC columns. Further on examining the interactive effects of different factors, we found a stronger interaction effect of sex by diet on metabolic phenotype. Interestingly, background strain had a moderate influence on collective metabolites irrespective of sex and age of mice.ConclusionOur initial results suggest that HFD is a major factor in defining the metabolic profile in AD mice above background strain, that could affect AD pathophysiology. We are currently looking into various classes of metabolites altered following HFD feeding and performing metabolic pathway analysis to understand the underlying disease mechanisms.