Document text
Principal Investigator: Vivian G Cheung
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2024
Award: $1
Funding agency: National Institute on Aging
PROJECT SUMMARY
APOE4 is a major genetic risk factor for Alzheimer's Disease, which affects millions worldwide. In the United
States, over 60% of Alzheimer's patients carry at least one APOE4 allele. Despite three decades of research,
the absence of precision medicine targeting APOE4 remains a critical gap. Recent gene therapy
breakthroughs, like mRNA vaccines and antisense oligonucleotide-based medicine, raise hope for APOE-
focused Alzheimer's treatments.
The APOE gene has three common alleles, E2, E3 and E4. APOE3 is the common allele, and it is not
associated with susceptibility to Alzheimer’s Disease. APOE4 is the ancestral allele; although it is the
susceptibility allele, its frequency has remained high suggesting potential selective advantages. APOE4 and
APOE3 alleles are distinguished by a single base difference (C vs. T at SNP rs429358). APOE4 exhibits a
dominant-like effect, elevating Alzheimer’s Disease risk in individuals with just one copy of the E4 allele.
Even with intense searches for treatments, precision medicine for this devastating disease remains elusive.
An incomplete understanding of the regulation of APOE expression and function may have contributed to this
therapeutic gap. Precision therapeutics targeting APOE4 while minimizing side effects demand a
comprehensive mechanistic understanding of APOE expression regulation and function.
Our recent discovery of the enhancer RNA, APOE-activating noncoding RNA (AANCR) is a significant
advance, shedding light on cell-type specific APOE expression and its stress responses. This discovery
provides critical insights into APOE expression regulation and susceptibility to Alzheimer’s Disease. Our
project aims to elucidate how AANCR regulates APOE transcription and how AANCR itself is modulated to
maintain cell-type specific and stress-induced APOE expression.
Notably, we observed APOE induction in the central nervous system during stress. To advance APOE-
targeted interventions, understanding its stress-induced functions is imperative. In stress-activated astrocytes
and microglia, we will assess how APOE expression and genotypes affect cellular function. Multiomic
analyses will investigate cytokine levels, gene expression patterns, and lipid profiles to characterize the
function of APOE. Subsequent co-culture experiments will assess the effects of APOE and these associated
factors on neuronal health, including synaptic activity and survival.
Leveraging our RNA, genetics, and neurobiology expertise, along with preliminary data, we are uniquely
poised to address these critical knowledge gaps. Our project integrates a thorough understanding of APOE
regulation in homeostasis and stress response with its broader implications on neuronal health. This dual
focus is crucial for developing targeted, effective treatment for Alzheimer's Disease.
Terms: <AD dementia><APOE e4><APOE-ε4><APOEε4><Address><Affect><Alleles><Allelomorphs><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer risk factor><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's disease patient><Alzheimer's disease risk><Alzheimer's disease therapeutic><Alzheimer's patient><Alzheimer's therapeutic><Alzheimers Dementia><American><Antisense Agent><Antisense Oligonucleotides><Apo-E><ApoE><ApoE protein><Apolipoprotein E><Aran-Duchenne disease><Assay><Astrocytes><Astrocytus><Astroglia><Autoregulation><Basal Transcription Factor><Basal transcription factor genes><Binding><Binding Proteins><Bioassay><Biological Assay><CNS Nervous System><Cell Body><Cell Function><Cell Physiology><Cell Process><Cells><Cellular Function><Cellular Physiology><Cellular Process><Central Nervous System><Chemicals><Co-culture><Cocultivation><Coculture><Coculture Techniques><Complex><Cruveilhier disease><DNA Therapy><Data><Disease><Disorder><Enhancers><Exhibits><Expression Signature><Frequencies><Functional RNA><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profile><Gene Expression Profiling><Gene Transcription><Gene Transfer Clinical><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic><Genetic Intervention><Genetic Transcription><Genetic predisposing factor><Genotype><Health><Healthcare><Hi-C><Homeostasis><Hortega cell><Human><Immune Precipitation><Immunoprecipitation><Individual><Intervention><Intervention Strategies><Knowledge><Late Onset Alzheimer Disease><Ligand Binding Protein><Ligand Binding Protein Gene><Light><Lipids><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mediator><Medicine><Metabolic Protein Degradation><Microglia><Modern Man><Molecular Interaction><Nerve Cells><Nerve Unit><Neural Cell><Neuraxis><Neurobiology><Neurocyte><Neurons><Non-Coding><Non-Coding RNA><Non-Polyadenylated RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Patients><Persons><Photoradiation><Physiological Homeostasis><Play><Precision therapeutics><Predisposition><Predisposition gene><Primary Senile Degenerative Dementia><Protein Binding><Protein Turnover><Proteins><RNA><RNA Expression><RNA Gene Products><RNA Seq><RNA Splicing><RNA sequencing><RNA vaccine><RNA-based vaccine><RNAseq><Regulation><Regulatory Protein><Regulatory Protein Degradation><Research><Ribonucleic Acid><Risk Factors><Role><SMN2><SMN2 gene><Signal Pathway><Spinal Muscular Atrophy><Splicing><Stress><Subcellular Process><Susceptibility><Susceptibility Gene><Synapses><Synaptic><Therapeutic><Transcript Expression Analyses><Transcript Expression Analysis><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Translating><United States><Untranslated RNA><alzheimer risk><analyze gene expression><antisense oligo><apo E-3><apo E-4><apo E3><apo E4><apo epsilon4><apoE epsilon 4><apoE-3><apoE-4><apoE3><apoE4><apolipoprotein E epsilon 4><apolipoprotein E-3><apolipoprotein E-4><apolipoprotein E3><apolipoprotein E4><astrocytic glia><base><bases><biological adaptation to stress><bound protein><cell type><cost><cytokine><design><designing><effective therapy><effective treatment><experiment><experimental research><experimental study><experiments><gene expression analysis><gene expression assay><gene expression pattern><gene expression signature><gene repair therapy><gene therapy><gene-based therapy><genetic regulatory protein><genetic risk factor><genetic therapy><genomic therapy><gitter cell><health care><inherited factor><inhibitor><insight><interventional strategy><knock-down><knockdown><late onset alzheimer><lipidomics><mRNA vaccine><mRNA-based vaccine><mesoglia><microglial cell><microgliocyte><multiomics><multiple omics><neurobiological><neuron toxicity><neuronal><neuronal toxicity><neurotoxicity><noncoding><panomics><patient living with Alzheimer's disease><patient suffering from Alzheimer's disease><patient with Alzheimer's><patient with Alzheimer's disease><perivascular glial cell><precision medicine><precision therapies><precision treatment><precision-based medicine><predisposing gene><primary degenerative dementia><protein degradation><reaction; crisis><regulatory gene product><response><senile dementia of the Alzheimer type><side effect><social role><stress response><stress; reaction><survival of motor neuron 2><susceptibility allele><susceptibility locus><susceptibility variant><synapse><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><transcription factor><transcriptional profile><transcriptional profiling><transcriptional signature><transcriptome sequencing><transcriptomic sequencing>