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  Glial and vascular contributions to neurodegenerative diseases
  Materials and methods: We utilized CRISPR to create a novel knock in (KI) mouse carrying the Mthfr677C>T allele on the C57BL/6J background. Liver and brain enzyme function were assessed in young Mthfr677C>T mice while plasma homocysteine was measured both in young and aged cohorts. Immunohistochemistry, electron microscopy and PET/CT were used to examine cerebrovascular density, morphology and function, respectively.
Results: Mthfr677C>T mice have reduced liver and brain enzymatic function and increased plasma homocysteine levels, which corresponds to human data. Young mice carrying one or two risk alleles show significantly reduced vascular density and increased glial activation in frontal cortex as well as reduced blood perfusion in several brain regions. Cerebrovascular ultrastructure shows endothelial and pericyte apoptosis, reduced luminal size, and increased astrocyte and microglial presence in the microenvironment.
Discussion: Vascular contributions to AD and related dementias are increasingly being recognized in the field as a critical component to the complex pathology. The Mthfr677C>T model provides clues as to how early changes in vascular function could initiate and promote subsequent neurodegeneration.
Conclusions: A novel mouse strain has been created to determine mechanisms by which the MTHFR677C>T polymorphism increases risk for cerebrovascular dysfunction. This work aims to identify novel therapeutic approaches that reduce cerebrovascular pathology in AD and other dementias.
determine to what extent is due to neuronal injury/neuroinflammation/ AD pathology and whether it correlates with the progression of subclinical atherosclerosis and with cognitive deficits and changes in brain anatomy/perfusion. This study would be an important step forward in our knowledge to develop preventive interventions to reduce the incidence of AD.
October 10, 2022, 17:00 - 18:00
Expression quantitative trait locus (eQTL) studies have been instrumental in pinpointing the functional genes and identifying drug targets for complex diseases. We and others have demonstrated that QTLs using other omic layers (proteins, metabolites, and lipids) do not overlap with eQTL and provide a biological context for additional GWAS loci. Cerebrospinal fluid (CSF) biomarkers are one of primary diagnostic tools in Alzheimer’s disease (AD), highlighting CSF’s relevance to brain aging and AD pathology. Here, we present a large-scale CSF pQTL and metabQTL analysis of over 3,000 individuals.
We generated proteomics (Somalogic; 7,584 proteins) and metabolomics (Metabolon; 440 analytes) data for 3,065 individuals in CSF. We performed QTL analysis using, in three stages: discovery, replication, and meta-analyses. We performed colocalization of our QTLs with GWAS for AD risk. Mendelian randomization (MR), protein- wide and metabolite-wide association study (PWAS/MWAS) using FUSION was performed to identify proteins and metabolites that are causal for AD.
We identified a total of 2,472 significant pQTL (1,297 in cis and 1,175 in trans), of which 1,339 are novel. Of the 99 GWAS loci for AD risk, 68 had a pQTL with suggestive significance (1×10-5) and 36 with genome-wide significance (5×10-8). PWAS analyses identified over 25 proteins causal for AD enriched in multiple pathways including amyloid beta metabolism (APOE, ACE and CNTN2), endolysosomal (GRN, CTSH, CLN5 among others) and immune pathway (TREM2, CD33, IL34 among others). We identified 192 (113 novel) metabQTL. 16 metabQTL colocalized with AD risk loci and are enriched on cortisol and sphingomyelinase cholesterol pathways.
This study represents the largest QTL analysis of CSF to date and identified hundreds of novel pQTL and metabQTL. Many of our CSF pQTLs were distinctive from recently published plasma pQTLs, indicating the presence of many tissue-specific signals. We also identified several causal and druggable proteins and metabolites for AD.
Genome wide association studies of Alzheimer’s disease (AD) patient mutations strongly implicate immune pathways in disease onset or progression. In the healthy brain, microglia, primary immune cells of the brain, ensure nervous system well-being and function by eliminating dying cells, pruning synapses, and orchestrating appropriate immune responses. Multiple lines of evidence indicate that two essential
Large-scale multi-omic analyses in CSF identified several causal and druggable targets for Alzheimer’s disease
Carlos Cruchaga1
1Washington Unversity, USA
Understanding the impact of midlife cardiovascular risk factors & subclinical atherosclerosis on brain´s health: a role on Alzheimer´s pathology
Marta Cortes-Canteli1,2, Juan Domingo Gispert1,3, Catarina Tristão-Pereira1, Fatima Sanchez-Cabo1, Marc Suarez-Calvet3, Michael Schöll4, Borja Ibanez1,2, Henrik Zetterberg4, Kaj Blennow4, Valentin Fuster1
1Centro Nacional De Investigaciones Cardiovasculares, Madrid, Spain 2Instituto De Investigacion Sanitaria Fundacion Jimenez Diaz, Madrid, Spain 3BarcelonaBeta Research Centre, Barcelona, Spain
4University of Gothenburg, Sweden
 Genetic and epidemiological studies have consistently reported that cardiovascular risk factors (CVRFs) increase the risk for Alzheimer’s Disease (AD). Like cardiovascular disease (CVD), AD has a long preclinical stage that extends decades. While the contribution of cerebrovascular disease to clinical severity of cognitive decline is well-established, the role of CVRFs in the development of AD pathogenesis is essentially unknown. To understand the interrelationship between these diseases at the preclinical level a longitudinal study is needed that evaluates their courses in asymptomatic stages. The Progression of Early Subclinical Atherosclerosis is a prospective study with the goal of tracking the trajectories of atherosclerosis and other CVDs from early stages to the transition to symptomatic phases in middle-aged asymptomatic individuals during two decades. Results from the baseline visit indicate that subclinical atherosclerosis is already highly prevalent in this “healthy” middle-aged cohort. Interestingly, we found that in those PESA individuals with subclinical atherosclerosis, cardiovascular risk is associated with lower cerebral 18F-fluorodeoxy-glucose (FDG) uptake detected by positron emission tomography in regions known to be hypometabolic in AD. The presence of hypertension was the modifiable CVRF showing the strongest association in the cingulate gyri and subclinical carotid plaque burden was also linked to reduced FDG uptake in parietal regions, even independently of CVRFs. This is the first time a direct relationship between the presence of atherosclerosis and reduced levels of a functional biomarker of neuronal health has been described in asymptomatic middle-aged individuals. We now plan to decipher whether this brain hypometabolism has progressed and
  48 • ISMND 2022
Lysosomal signaling in microglia and Alzheimer’s disease
Harini Iyer1, William Talbot1
1Stanford University, USA

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