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Principal Investigator: Amy Dunn
Organization: JACKSON LABORATORY
Fiscal Year: 2024
Award: $849,854
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY
Alzheimer’s disease is the most common cause of dementia in the elderly, but there are a number of other
related dementias that exhibit substantial overlap in the behavioral, cognitive, and neuropathological
manifestations of the disease. In fact, the majority of dementia cases likely arise from the co-occurrence of one
or more of these AD and AD-related pathologies, with very few individuals exhibiting ‘pure’ Alzheimer’s
pathology (e.g., only amyloid plaques). This complexity makes diagnosis and therapeutic development
challenging, a problem exacerbated by a paucity of accurate animal models for ADRD that faithfully
recapitulate the full spectrum of the molecular, cellular, cognitive, and behavioral pathologies of these
dementias. In response to PAR-19-167, we will create a panel of genetically diverse knock-in mice harboring
known mutations associated with AD and several related dementias using precise genomic editing to ensure
biologically-relevant gene expression patterns and levels. In Aim 1, we will use CRISPR/Cas9 to create mice
carrying combinations of disease-causing mutations in App, Psen1, Mapt, Tardbp, and Snca to produce a set
of ‘core’ strains we expect to better capture the complexity of ADRD. To capture the role of genetic background
in disease risk, we will then cross these ‘core’ mice to four genetic backgrounds known to promote
susceptibility or resilience of ADRD (DBA/2J, FVB/NJ, WSB/EiJ, and C57Bl/6J). We will then leverage our
expertise in high-throughput mouse neurobehavioral phenotyping to screen 16 new ADRD strains to identify
the lines that best model ADRD. In Aim 2, we will use our deep phenotyping pipeline to fully characterize our
top strains across the entire spectrum of ADRD-related symptoms, including both cognitive and non-cognitive
domains. We will also use high-field MRI, histopathological measurements, and molecular phenotypes to
assess effects on brain structure, extent of neuropathologies, and impact on gene networks and pathways
associated with disease. Finally, in Aim 3, we will validate our new models for use in basic science and
preclinical studies by determining concordance between mouse and human data and use network modeling
approaches to identify early drivers of disease that predict late-stage outcomes in humans. This project will
produce much-needed new models for AD and related dementias that will greatly enhance our understanding
of the pathological mechanisms underlying these diseases. Finally, all of the models produced here will be
distributed to the community via the JAX Repository. We will also make all of the phenotyping data publicly
available using resources such as Mouse Phenome Database, GeneWeaver, and Synapse.
Terms: <AD dementia><AD model><AD pathology><AD related dementia><ADRD><Algorithmic Analyses><Algorithmic Analysis><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer risk factor><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 model><Alzheimer's disease or a related dementia><Alzheimer's disease or a related disorder><Alzheimer's disease or related dementia><Alzheimer's disease pathology><Alzheimer's disease related dementia><Alzheimer's disease risk><Alzheimer's pathology><Alzheimers Dementia><Amentia><Amyloid><Amyloid (Aβ) plaques><Amyloid Plaques><Amyloid Substance><Analyses of Algorithms><Analysis of Algorithms><Animal Model><Animal Models and Related Studies><Arteriosclerotic Dementia><Atlases><Basic Research><Basic Science><Behavioral><Blood Vessels><Body Tissues><Brain><Brain Nervous System><CRISPR><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 system><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cas nuclease technology><Cell Body><Cells><Cerebral Amyloid Angiopathy><Clinical Trials><Clustered Regularly Interspaced Short Palindromic Repeats><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><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive deficits><Cognitive function abnormal><Communities><Complex><Computer software><Congophilic Angiopathy><Coupled><Data><Data Bases><Databases><Degenerative Neurologic Disorders><Dementia><Diagnosis><Diet><Dimensions><Disease><Disease Progression><Disorder><Disturbance in cognition><Early identification><Elderly><Encephalon><Ensure><Environment><Environmental Exposure><Environmental Factor><Environmental Risk Factor><Exhibits><Expression Signature><Fecundability><Fecundity><Fertility><Frontal Temporal Dementia><Frontotemporal Dementia><Funding Mechanisms><Gene Expression Profile><Genetic><Genetic Alteration><Genetic Change><Genetic Diversity><Genetic Variation><Genetic defect><Health><Heterogeneity><Human><Image><Impaired cognition><Individual><Informatics><KI mice><Knock-in><Knock-in Mouse><LB dementia><Late Onset Alzheimer Disease><Lewy Body Dementia><Lewy Body Type Senile Dementia><Lewy dementia><MR Imaging><MR Tomography><MRI><MRIs><MT-bound tau><Magnetic Resonance Imaging><Measurement><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Memory Loss><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Murine><Mus><Mutation><NAC precursor><NIH><NMR Imaging><NMR Tomography><National Institutes of Health><Nervous System Degenerative Diseases><Network Analysis><Neural Degenerative Diseases><Neural degenerative Disorders><Neuritic Plaques><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic><Neurologic Degenerative Conditions><Neurological><Non-Polyadenylated RNA><Nuclear Magnetic Resonance Imaging><Outcome><PARK1 protein><PARK4 protein><Pathogenesis><Pathologic><Pathology><Pathway Analysis><Pathway interactions><Patients><Pattern><Peripheral><Phase><Phenotype><Physiologic><Physiological><Population><Position><Positioning Attribute><Preclinical Testing><Predisposition><Primary Senile Degenerative Dementia><Process><RNA><RNA Gene Products><RNA Seq><RNA sequencing><RNAseq><Reproducibility><Research Resources><Resources><Rest><Ribonucleic Acid><Risk><Risk-associated variant><Role><Route><SNCA><SNCA protein><Selection Criteria><Senile Plaques><Severity of illness><Software><Staging><Structure><Susceptibility><Symptoms><Synapses><Synaptic><TAR DNA-binding protein 43><TDP-43><TDP43><Time><Tissues><Translating><Translations><United States National Institutes of Health><Variant><Variation><Vascular Dementia><Viral><Zeugmatography><a-syn><a-synuclein><advanced age><alpha synuclein><alpha synuclein gene><alphaSP22><alzheimer model><alzheimer risk><amyloid beta plaque><amyloid pathology><amyloid-b plaque><asyn><aβ plaques><behavior test><behavioral test><cerebrovascular amyloidosis><co-morbid><co-morbidity><cognitive assessment><cognitive defects><cognitive dysfunction><cognitive loss><cognitive testing><cohort><combinatorial><comorbidity><cored plaque><data base><data resource><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><depository><diets><diffuse plaque><disease causing variant><disease risk><disease severity><disease-causing mutation><disorder risk><drug discovery><environmental risk><familial AD><familial Alzheimer><familial Alzheimer disease><feature detection><feature recognition><front temporal dementia><frontal lobe dementia><frontotemporal lobar dementia><frontotemporal lobe degeneration associated with dementia><functional genomics><gene conservation><gene expression pattern><gene expression signature><gene network><genome editing><genome mutation><genomic data><genomic data-set><genomic dataset><genomic editing><geriatric><hippocampal sclerosis><human data><human disease><human model><image processing><imaging><improved><insight><knockin><knockin mice><late life><late onset alzheimer><life span><lifespan><memory decline><microtubule bound tau><microtubule-bound tau><mimetics><mixed dementia><mixed etiology dementia><mixed pathology dementia><mixed type dementia><model development><model developments><model of animal><model of human><molecular phenotype><mouse genetics><mouse model><multiple etiology dementia><multiple pathology dementia><multiple type dementia><murine model><network models><neural imaging><neuro-imaging><neurobehavioral><neurodegenerative illness><neuroimaging><neurological imaging><neuropathologic><neuropathological><neuropathology><neurotoxic><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><next generation><non A-beta component of AD amyloid><non A4 component of amyloid precursor><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><pathogenic variant><pathway><phenome><phenotypic data><pre-clinical study><pre-clinical testing><preclinical study><primary degenerative dementia><programs><protein TDP-43><protein TDP43><repository><resilience><resilient><response><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><screening><screenings><senile dementia of the Alzheimer type><senior citizen><sex><social role><synapse><synucleinopathy><tau><tau Proteins><tau factor><therapeutic agent development><therapeutic development><transcriptional profile><transcriptional signature><transcriptome sequencing><transcriptomic sequencing><translation><vascular><vascular contributions to dementia><western diet><western-style diet><western-type diet><α synuclein gene><α-syn><α-synuclein><τ Proteins>