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Principal Investigator: Matt Huentelman
Organization: ST. JOSEPH'S HOSPITAL AND MEDICAL CENTER
Fiscal Year: 2024
Award: $64,322
Funding agency: National Institute of Neurological Disorders and Stroke
Project Abstract
The role of microglia in the C9orf72 (C9) amyotrophic lateral sclerosis (ALS)/ frontotemporal dementia (FTD)
disease spectrum remains poorly understood. Early investigations found that microglia activation was
significantly higher in ALS with dementia and impaired executive function, suggesting that microglia activation
correlates with FTD-like symptoms in ALS. More recent neuropathologic examinations of microglia in FTLD
patient autopsy brains with mutations in progranulin versus C9orf72 concluded that the observed microglia
dysfunction was different between the two genetically different patient subgroups suggesting specificity of
microglia dysfunction depending on the etiology of the patient population. One interesting aspect of microglia-
neuron communication is the role of microglia in the maintenance and refinement of synaptic networks through
the selective pruning of synapses, which occurs predominantly during development but has been shown to also
be triggered in Alzheimer's disease (AD) and related dementias, including FTD. The degree of synapse loss in
AD strongly correlates with cognitive decline, even more than the amount of plaque, tangles or neuronal loss,
and a recent study of ALS postmortem tissue confirmed increased synapse loss in the prefrontal cortex of
patients with reported cognitive impairments. Our laboratory has preliminary data supporting the hypothesis that
there is an altered neural-immune interaction in the cortical forebrain regions of C9orf72 patients with
confirmed FTD in which microglia and neurons modify each other's function. Using patient-derived hiPSC
microglia and cortical neurons, we are able to show that C9 patient-derived hiPSC microglia mono-cultures do
have intrinsic phenotypes, including altered gene profiles, phagocytic activities and lysosomal function. Most
interestingly, preliminary data suggests that C9 microglia do regulate neuronal excitability and survival of C9
iPSC neurons. To further investigate the role and contribution of microglia in C9 cortical degeneration, we
propose to thoroughly investigate the intrinsic properties of C9 hiPSC-microglia (from all patient subgroups: FTD,
FTD/ALS, ALS; Aim1). For the first time, we will then co-culture these microglia with C9 and healthy control
hiPSC cortical neurons to better understand the co-regulation between these two cell types (Aim 2). Finally, in
the third aim, we will study microglia activation and pathology in C9 patient postmortem autopsy tissue. This will
include cell-type specific genetic profiling from existing snRNA seq data sets, immunohistochemistry of
microgliosis and multi-label immunostaining for microglial-specific candidate genes/proteins in conjunction with
C9 neuronal disease pathology markers (TDP-43 and C9 DPRs) to gain novel knowledge on whether microglia
are preferentially altered in close vicinity to neuronal pathologies.
Terms: <AD dementia><AD related dementia><ADRD><Affect><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's and related dementias><Alzheimer's disease and related dementia><Alzheimer's disease and related disorders><Alzheimer's disease or a related dementia><Alzheimer's disease or a related disorder><Alzheimer's disease or related dementia><Alzheimer's disease related dementia><Alzheimers Dementia><Amentia><Amyotrophic Lateral Sclerosis><Amyotrophic Lateral Sclerosis Motor Neuron Disease><Amyotrophic lateral sclerosis and frontotemporal degeneration><Amyotrophic lateral sclerosis and frontotemporal dementia><Area><Astrocytes><Astrocytus><Astroglia><Autopsy><Body Tissues><Brain><Brain Nervous System><Brain region><C9ALS><C9ALS/FTD><C9ORF72><Candidate Disease Gene><Candidate Gene><Causality><Cell Body><Cell Differentiation><Cell Differentiation process><Cell Line><CellLine><Cells><Chemotactic Cytokines><Clinical><Co-culture><Cocultivation><Coculture><Coculture Techniques><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Communication><Data><Data Set><Degenerative Neurologic Disorders><Dementia><Department of Defense><Development><Differential Gene Expression><Dipeptides><Disease><Disorder><Disturbance in cognition><Drug Targeting><Dysfunction><Encephalon><Etiology><Executive Dysfunction><Executive Function Deficit><Executive Impairment><Expression Profiling><Expression Signature><FTD/ALS><FTLD><FTLD/ALS><Fore-Brain><Forebrain><Frontal Temporal Dementia><Frontotemporal Dementia><Frontotemporal Lobar Degeneration/Amyotrophic lateral sclerosis><Frontotemporal Lobar Degenerations><Frontotemporal variety lobar degeneration><Functional disorder><Funding><Future><Gehrig's Disease><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profile><Gene Expression Profiling><Genes><Genetic Alteration><Genetic Change><Genetic defect><Gliosis><Goals><Homologous Chemotactic Cytokines><Hortega cell><Hot Spot><Human><Immune><Immunes><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Impaired cognition><In Vitro><Induced pluripotent stem cell derived neurons><Intercrines><Investigation><Knowledge><Label><Laboratories><Lou Gehrig Disease><Lysosomes><Maintenance><Measures><Microglia><Modeling><Modern Man><Molecular><Morphology><Motor Cell><Motor Neurons><Mutation><Nerve Cells><Nerve Degeneration><Nerve Unit><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurofibrillary Tangles><Neurologic Degenerative Conditions><Neuron Degeneration><Neuron from iPSC><Neuron from induced pluripotent stem cells><Neuronal Dysfunction><Neurons><Non-Polyadenylated RNA><Outcome><PC cell-derived growth factor><PCDGF><PGRN gene><PGRN protein><Pathogenesis><Pathologic><Pathology><Patients><Phagocytes><Phagocytic Cell><Phenotype><Physiopathology><Prefrontal Cortex><Primary Senile Degenerative Dementia><Process><Progranulin><Property><Prosencephalon><Proteins><RNA><RNA Gene Products><RNA Seq><RNA sequencing><RNAseq><Reporting><Ribonucleic Acid><Role><SIS cytokines><Single-Nucleus Sequencing><Specificity><Strains Cell Lines><Symptoms><Synapses><Synaptic><System><TAR DNA-binding protein 43><TDP-43><TDP43><Time><Tissue-Specific Differential Gene Expression><Tissue-Specific Gene Expression><Tissues><Transcript Expression Analyses><Transcript Expression Analysis><Validation><Variant><Variation><amebocyte><amyotrophic lateral sclerosis with frontotemporal dementia><amyotrophic lateral sclerosis/FTLD><amyotrophic lateral sclerosis/frontotemporal dementia><amyotrophic lateral sclerosis/ftd><analyze gene expression><astrocytic glia><c9FTD/ALS><c9als/frontotemporal dementia><c9ftd/amyotrophic lateral sclerosis><causation><cell cortex><cell type><cellular differentiation><chemoattractant cytokine><chemokine><chromosome 9 open reading frame 72><clinical diagnosis><cognitive dysfunction><cognitive loss><cultured cell line><cytokine><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><density><developmental><differentiation of pluripotent stem cells><disease causation><disease phenotype><drug discovery><executive control><executive function><front temporal dementia><frontal lobe dementia><frontotemporal dementia-amyotrophic lateral sclerosis><frontotemporal lobar dementia><frontotemporal lobar dementia amyotrophic lateral sclerosis><frontotemporal lobe degeneration associated with dementia><gene expression analysis><gene expression assay><gene expression pattern><gene expression signature><genetic profiling><genome mutation><gitter cell><global gene expression><global transcription profile><granulin precursor><hiPSC><human iPS><human iPSC><human induced pluripotent cell><human induced pluripotent stem cells><human inducible stem cells><iPS neurons><iPSC derived-neurons><induced human pluripotent stem cells><induced pluripotent stem cell neurons><induced pluripotent stem cells derived from patients><induced pluripotent stem cells from patients><mesoglia><microglial cell><microgliocyte><molecular phenotype><motoneuron><necropsy><nerve cell death><nerve cell loss><neural><neural degeneration><neural dysfunction><neurodegeneration><neurodegenerative><neurodegenerative illness><neurofibrillary degeneration><neurofibrillary lesion><neurofibrillary pathology><neurological degeneration><neuron cell death><neuron cell loss><neuron death><neuron loss><neuronal><neuronal cell death><neuronal cell loss><neuronal death><neuronal degeneration><neuronal excitability><neuronal loss><neuronal survival><neurons derived from induced pluripotent stem cells><neuropathologic><neuropathological><neuropathology><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pathophysiology><patient derived human iPS><patient derived human iPSC><patient derived human induced pluripotent stem cell><patient derived iPS><patient derived iPSC><patient derived induced pluripotent cells><patient derived induced pluripotent stem cells><patient population><patient subclass><patient subcluster><patient subgroups><patient subpopulations><patient subsets><patient subtypes><patient-derived pluripotent stem cells><perivascular glial cell><pluripotent stem cell differentiation><postmortem><primary degenerative dementia><progranulin gene><progranulin protein><protein TDP-43><protein TDP43><protein expression><sNuc-Seq><scRNA-seq><senile dementia of the Alzheimer type><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single nucleus RNA-sequencing><single nucleus seq><single-cell RNA sequencing><single-nucleus RNA-seq><snRNA sequencing><snRNA-seq><social role><synapse><tangle><transcriptional profile><transcriptional profiling><transcriptional signature><transcriptome><transcriptome sequencing><transcriptomic sequencing><validations>