Physiology Commons^™

Apoε4 Lowers Energy Expenditure In Females And Impairs Glucose Oxidation By Increasing Flux Through Aerobic Glycolysis, Brandon C. Farmer, Holden C. Williams, Nicholas A. Devanney, Margaret A. Piron, Grant K. Nation, David J. Carter, Adeline E. Walsh, Rebika Khanal, Lyndsay E. A. Young, Jude C. Kluemper, Gabriela Hernandez, Elizabeth J. Allenger, Rachel Mooney, Lesley R. Golden, Cathryn T. Smith, J. Anthony Brandon, Vedant A. Gupta, Philip A. Kern, Matthew S. Gentry, Josh M. Morganti, Ramon C. Sun, Lance A. Johnson

Physiology Faculty Publications

BACKGROUND: Cerebral glucose hypometabolism is consistently observed in individuals with Alzheimer's disease (AD), as well as in young cognitively normal carriers of the Ε4 allele of Apolipoprotein E (APOE), the strongest genetic predictor of late-onset AD. While this clinical feature has been described for over two decades, the mechanism underlying these changes in cerebral glucose metabolism remains a critical knowledge gap in the field.

METHODS: Here, we undertook a multi-omic approach by combining single-cell RNA sequencing (scRNAseq) and stable isotope resolved metabolomics (SIRM) to define a metabolic rewiring across astrocytes, brain tissue, mice, and human subjects expressing APOE4.

RESULTS: Single-cell …

Alzheimer's Disease Genetics And Abca7 Splicing, Jared B. Vasquez, James F. Simpson, Ryan Harpole, Steven Estus

Physiology Faculty Publications

Both common and rare polymorphisms within ABCA7 have been associated with Alzheimer’s disease (AD). In particular, the rare AD associated polymorphism rs200538373 was associated with altered ABCA7 exon 41 splicing and an AD risk odds ratio of ∼1.9. To probe the role of this polymorphism in ABCA7 splicing, we used minigene studies and qPCR of human brain RNA. We report aberrant ABCA7 exon 41 splicing in the brain of a carrier of the rs200538373 minor C allele. Moreover, minigene studies show that rs200538373 acts as a robust functional variant in vitro. Lastly, although the ABCA7 isoform with an extended …

Predominant Expression Of Alzheimer’S Disease-Associated Bin1 In Mature Oligodendrocytes And Localization To White Matter Tracts, Pierre De Rossi, Virginie Buggia-Prévot, Benjamin L. L. Clayton, Jared B. Vasquez, Carson Van Sanford, Robert J. Andrew, Ruben Lesnick, Alexandra Botté, Carole Deyts, Someya Salem, Eshaan Rao, Richard C. Rice, Angèle Parent, Satyabrata Kar, Brian Popko, Peter Pytel, Steven Estus, Gopal Thinakaran

Physiology Faculty Publications

Background: Genome-wide association studies have identified BIN1 within the second most significant susceptibility locus in late-onset Alzheimer’s disease (AD). BIN1 undergoes complex alternative splicing to generate multiple isoforms with diverse functions in multiple cellular processes including endocytosis and membrane remodeling. An increase in BIN1 expression in AD and an interaction between BIN1 and Tau have been reported. However, disparate descriptions of BIN1 expression and localization in the brain previously reported in the literature and the lack of clarity on brain BIN1 isoforms present formidable challenges to our understanding of how genetic variants in BIN1 increase the risk for AD.

Methods: …

Genetics Ignite Focus On Microglial Inflammation In Alzheimer's Disease, Manasi Malik, Ishita Parikh, Jared B. Vasquez, Conor Smith, Leon Tai, Guojun Bu, Mary Jo Ladu, David W. Fardo, G. William Rebeck, Steven Estus

Physiology Faculty Publications

In the past five years, a series of large-scale genetic studies have revealed novel risk factors for Alzheimer's disease (AD). Analyses of these risk factors have focused attention upon the role of immune processes in AD, specifically microglial function. In this review, we discuss interpretation of genetic studies. We then focus upon six genes implicated by AD genetics that impact microglial function: TREM2, CD33, CR1, ABCA7, SHIP1, and APOE. We review the literature regarding the biological functions of these six proteins and their putative role in AD pathogenesis. We then present a model for how …

Determining The Role Of Il-4 Induced Neuroinflammation In Microglial Activity And Amyloid-Ss Using Bv2 Microglial Cells And App/Ps1 Transgenic Mice, Clare H. Latta, Tiffany L. Sudduth, Erica M. Weekman, Holly M. Brothers, Erin L. Abner, Gabriel J. Popa, Michael D. Mendenhall, Floracita Gonzalez-Oregon, Kaitlyn Braun, Donna M. Wilcock

Physiology Faculty Publications

Background

Microglia are considered the resident immune cells of the central nervous system (CNS). In response to harmful stimuli, an inflammatory reaction ensues in which microglia are activated in a sequenced spectrum of pro- and antiinflammatory phenotypes that are akin to the well-characterized polarization states of peripheral macrophages. A “classically” activated M1 phenotype is known to eradicate toxicity. The transition to an “alternatively” activated M2 phenotype encompasses neuroprotection and repair. In recent years, inflammation has been considered an accompanying pathology in response to the accumulation of extracellular amyloid-β (Aβ) in Alzheimer’s disease (AD). This study aimed to drive an M2a-biased …