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Principal Investigator: Na Zhao
Organization: MAYO CLINIC JACKSONVILLE
Fiscal Year: 2024
Award: $742,112
Funding agency: National Institute on Aging
PROJECT SUMMARY
The major goal of this proposal is to address the dynamic role of TREM2-mediated microglial function in
brain aging and during different stages of the pathological development of Alzheimer’s disease (AD). TREM2 is
a microglial specific gene with several of its rare variants associated with AD risk. Despite some progress, the
molecular pathobiology of TREM2 in particular the TREM2-R47H risk variant is still not clear. Studies
examining the effects of loss of TREM2 function in mouse models support inconsistent conclusions; with
TREM2 deficiency either reduces or enhances amyloid or tau pathology and associated toxicity depending on
the stage of the pathological development or the specific mouse models. As such, TREM2-mediated microglial
function likely has dynamic effects on amyloid and tau pathologies depending on pathological stages
throughout AD progression. Further complicating the challenge of studying the impact of TREM2-R47H variant,
a recent study revealed that introducing the R47H mutation into the mouse Trem2 gene locus leads to aberrant
splicing and instability of its mRNA. To fill these gaps in knowledge and the lack of appropriate model systems,
we have generated novel cell type-specific and inducible mouse models expressing human TREM2 or TREM2-
R47H in microglia. To address human relevance and molecular mechanisms, we have also generated human
induced pluripotent stem cell (iPSC) lines carrying TREM2 or TREM2-R47H. Thus, the major goal of this
proposal is to examine the dynamic effects of human TREM2 and TREM2-R47H on microglial and neuronal
functions in aging and AD; while in the process defines the underlying molecular pathways by targeted and
non-targeted approaches. We hypothesize that TREM2-mediated microglial function is protective against the
development of AD pathologies but can be detrimental when such pathologies are associated with synaptic
loss and neurodegeneration. We also hypothesize that TREM2-R47H represents a loss-of-function in particular
in microglia-mediated protection against AD-related pathways. We will test our hypothesis through three aims.
In Aim 1, we plan to analyze the effects of TREM2 or TREM2-R47H upon injury paradigms and during aging in
the absence of AD pathology. In Aim 2, we will examine the effects of TREM2 or TREM2-R47H on the
metabolism, deposition, and toxicity of Aβ and tau at different stages of pathological development. In Aim 3, we
plan to identify and validate the molecular pathways associated with TREM2 and TREM2-R47H using iPSC-
derived microglia-like cells with or without integration into cerebral organoids. This innovative proposal will take
advantage of our existing conditional mouse models and iPSC-derived cellular models combined with state-of-
the-art technologies including in vivo microdialysis, two-photon microscopy and molecular profiling by single
cell RNA-Seq. These efforts should collectively help to understand how TREM2 modulates microglial dynamic
roles in aging and AD pathogenesis and how we can target these pathways to treat AD.
Terms: <2-photon><2-photon microscopy><3-D><3-Dimensional><3D><65 and older><65 or older><65 years of age and older><65 years of age or more><65 years of age or older><65+ years><65+ years old><> 65 years><AD dementia><AD pathology><Abeta clearance><Address><Affect><Aged 65 and Over><Aging><Alleles><Allelomorphs><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease dementia><Alzheimer risk factor><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimer's disease pathology><Alzheimer's disease risk><Alzheimer's pathology><Alzheimers Dementia><Amentia><Amyloid><Amyloid (Aβ) plaques><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Plaques><Amyloid Protein A4><Amyloid Substance><Amyloid beta-Protein><Amyloid β><Amyloid β clearance><Amyloid β toxicity><Amyloid β-Peptide><Amyloid β-Protein><Apo-E><ApoE><ApoE protein><Apolipoprotein E><Aβ><Aβ clearance><Behavior><Biochemical><Biologic Models><Biological Models><Brain><Brain Nervous System><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cas nuclease technology><Causality><Cell Body><Cell Line><Cell model><CellLine><Cells><Cellular model><Cerebrum><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Cognitive><Dementia><Deposit><Deposition><Development><Disease><Disease Progression><Disorder><Electrophysiology><Electrophysiology (science)><Encephalon><Etiology><Future><Gene Delivery><Genes><Genetic Alteration><Genetic Change><Genetic defect><Genetic predisposing factor><Goals><Hortega cell><Human><Image><Immune><Immune response><Immunes><Immunological response><In Vitro><Inflammatory Response><Injury><Intermediary Metabolism><Knock-in><Knock-out><Knockout><Knowledge><MT-bound tau><Mediating><Messenger RNA><Metabolic Processes><Metabolism><Methods><Mice><Mice Mammals><Microdialysis><Microglia><Model System><Modeling><Modern Man><Molecular><Molecular Fingerprinting><Molecular Profiling><Molecular Target><Morphology><Murine><Mus><Mutation><Nerve Cells><Nerve Degeneration><Nerve Unit><Neural Cell><Neuritic Plaques><Neurocyte><Neuron Degeneration><Neurons><Neurophysiology / Electrophysiology><Organoids><Pathogenesis><Pathogenicity><Pathologic><Pathology><Pathway interactions><Phagocytosis><Population><Primary Senile Degenerative Dementia><Process><RNA Seq><RNA Splicing><RNA sequencing><RNAseq><Risk-associated variant><Role><Senile Plaques><Societies><Splicing><Strains Cell Lines><Synapses><Synaptic><System><TREM2><TREM2 gene><Tauopathies><Techniques><Technology><Testing><Toxic effect><Toxicities><Triggering Receptor Expressed in Myeloid Cells 2><Triggering Receptor Expressed on Myeloid Cells 2><Validation><Variant><Variation><a beta peptide><a-beta peptide clearance><abeta><abeta deposition><abeta peptide clearance><abeta toxicity><above age 65><after age 65><age 65 and greater><age 65 and older><age 65 or older><age > 65><age of 65 years onward><aged 65 and greater><aged 65+><aged brain><aged ≥65><aging brain><alzheimer risk><amyloid assembly><amyloid beta><amyloid beta clearance><amyloid beta deposition><amyloid beta peptide clearance><amyloid beta plaque><amyloid beta toxicity><amyloid formation><amyloid pathology><amyloid β deposition><amyloid-b plaque><amyloid-b protein><aβ deposition><aβ plaques><aβ toxicity><beta amyloid fibril><causation><cell type><cerebral><cored plaque><cultured cell line><density><developmental><diffuse plaque><disease causation><electrophysiological><gene editing platform><gene editing system><gene editing technology><gene editing tools><gene locus><gene-editing toolkit><genetic locus><genetic risk factor><genome mutation><genomic location><genomic locus><gitter cell><hiPSC><histopathologic examination><histopathological examination><host response><human iPS><human iPSC><human induced pluripotent cell><human induced pluripotent stem cells><human inducible stem cells><human model><human old age (65+)><iPS><iPSC><iPSCs><imaging><immune system response><immunoresponse><in vivo><in vivo Model><induced human pluripotent stem cells><induced pluripotent cell><induced pluripotent stem cell><inducible pluripotent stem cell><inherited factor><injuries><innovate><innovation><innovative><knockin><loss of function><mRNA><mesoglia><microglial cell><microgliocyte><microtubule bound tau><microtubule-bound tau><mid life><mid-life><middle age><middle aged><midlife><model of human><molecular profile><molecular signature><mouse model><murine model><neural degeneration><neurodegeneration><neurodegenerative><neurological degeneration><neuronal><neuronal degeneration><neuropathologic tau><neuropathological tau><novel><old age><over 65 years><pathway><perivascular glial cell><pharmacologic><primary degenerative dementia><progenitor cell model><progenitor model><rare allele><rare mutation><rare variant><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><scRNA-seq><senile dementia of the Alzheimer type><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><soluble amyloid precursor protein><stem and progenitor cell model><stem cell based model><stem cell derived model><stem cell model><synapse><tau><tau Proteins><tau associated neurodegeneration><tau associated neurodegenerative process><tau factor><tau induced neurodegeneration><tau mediated neurodegeneration><tau neurodegenerative disease><tau neuropathology><tauopathic neurodegenerative disorder><tauopathy><three dimensional><transcriptome sequencing><transcriptomic sequencing><treatment strategy><two photon excitation microscopy><two photon microscopy><two-photon><validations><τ Proteins><≥65 years>