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Principal Investigator: KENNETH Stephen KOSIK
Organization: UNIVERSITY OF CALIFORNIA SANTA BARBARA
Fiscal Year: 2024
Award: $619,969
Funding agency: National Institute on Aging
The complex interaction between Alzheimer drivers and aging
Project Summary/Abstract (30 lines of text)
The greatest risk for Alzheimer’s disease is age. This extremely tight correlation with age has
no explanation. However, most of what know about Alzheimer’s comes from early onset cases.
We will utilize the 100 cases of early onset AD stored in the Colombian brain bank all with the
same PSEN1[E280A] mutation to determine the full range of pathology observed due to a
monogenic defect and compare these data to sporadic older onset disease. Some of the
Colombian individuals in the bank have had amyloid and tau PET studies. In sporadic disease
among the elderly, brain changes related to aging are frequent and in the absence of their
clear delineation, treatments targeted solely at dominant genetic forms of the disease may be
ineffective. Factors which might distinguish and promote AD in the elderly include inflammation,
compromised brain vasculature, excessive microgliosis, cellular aging such as break down of
the nuclear membrane and consequently escape of TDP-43 from the nucleus and possible
contributions of synuclein. We will explore interactions of these factors with aging through
descriptive neuropathology and experimental neuropathology methods. Comparisons will utilize
sporadic AD post-mortem from several brain banks. These studies include state of the art
single cell RNAseq and advanced assessment of inflammation markers. Cellular models will be
explored using human induced pluripotent stem cell-derived neurons that harbor the
PSEN1[E280A] mutation and are intended to discover downstream pathways affected by the
mutation. Co-cultures with microglia to capture autonomous and non-autonomous effects of the
mutation will be determined.
To accomplish the aims we have assembled a multi-institutional international team with a long
history of collaboration. Dr. Lopera, who first recognized the families and manages the
Alzheimer Prevention Trial, heads the team in Colombia, an NIH supported project. To support
the neuropathology effort we have enlisted the expertise of Dr. Eric Huang. Kosik has a nearly
30 year collaboration with Lopera, is familiar with the conduct of research in Colombia and
recently traveled to visit the Colombian brain bank with Eric Huang. Kosik is closely connected
institutionally with UCSF through his role as co-director of the Tau Consortium along with Bruce
Miller. Kosik has published with Ellisman and serves on the review board for the National
Center for Microscopy and Imaging Research center at UCSD. Thus the project consists of a
strong, experienced and highly integrated team capable of conducting a complex project and
dealing with any of the obstacles that will inevitably arise.
Terms: <(TNF)-α><AD dementia><AD pathology><AD prevention><Acetylation><Adventitial Cell><Affect><Age><Aging><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer disease prevention><Alzheimer prevention><Alzheimer risk factor><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's disease pathology><Alzheimer's disease risk><Alzheimer's pathology><Alzheimers Dementia><Amyloid><Amyloid Substance><Antibodies><Astrocytes><Astrocytosis><Astrocytus><Astroglia><Astroprotein><Attention><Autopsy><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Basic Mechanisms of SUMOylation><Beta Proprotein Interleukin 1><Body Tissues><Brain><Brain Nervous System><CD31><CSPG4><CSPG4 gene><Cachectin><Cell Aging><Cell Body><Cell Differentiation><Cell Differentiation process><Cell Nucleus><Cell Senescence><Cell model><Cells><Cellular Aging><Cellular Senescence><Cellular model><Cerebrovascular system><Characteristics><Co-culture><Cocultivation><Coculture><Coculture Techniques><Collaborations><Collection><Colombia><Colombian><Complex><Cytoplasm><Data><Data Set><Defect><Disease><Disorder><Dominant Genetic Conditions><Dominant trait><EOAD><Early Onset Alzheimer Disease><Elderly><Encephalon><Extravasation><Family><Fibroblasts><GFA-Protein><GFAP><GWA study><GWAS><Gene Alteration><Gene Expression><Gene Mutation><Genes><Genetic Alteration><Genetic Change><Genetic Dominant><Genetic defect><Glial Fibrillary Acid Protein><Glial Fibrillary Acidic Protein><Glial Intermediate Filament Protein><Gliosis><HPGF><Hepatocyte-Stimulating Factor><History><Hortega cell><Human><Hybridoma Growth Factor><IFN-beta 2><IFNB2><IL-1 alpha><IL-1 beta><IL-1 β><IL-1-a><IL-1-b><IL-1A><IL-1alpha><IL-1α><IL-1β><IL-6><IL1-Alpha><IL1-Beta><IL1-α><IL1-β><IL1A Protein><IL1B Protein><IL1F1><IL1F2><IL1β><IL6 Protein><Image><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Individual><Induced pluripotent stem cell derived human neuron><Inflammation><Inflammatory><Institution><Interleukin 1alpha><Interleukin 1beta><Interleukin-1 alpha><Interleukin-1 beta><Interleukin-1β><Interleukin-6><International><Leakage><Leiomyocyte><Link><Literature><MCSPG><MEL-CSPG><MGI-2><MSK16><MT-bound tau><Macrophage-Derived TNF><Maryland><Mediating><Mendelian disease><Mendelian disorder><Mendelian genetic disorder><Methods><Microglia><Microscopy><Modern Man><Modification><Monocyte-Derived TNF><Mutation><Myeloid Differentiation-Inducing Protein><NAC precursor><NG2><NIH><National Institutes of Health><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><New York><Nuclear><Nuclear Envelope><Nuclear Membrane><Nucleus><Older Population><Onset of illness><PARK1 protein><PARK4 protein><PECAM1><PECAM1 gene><PET><PET Scan><PET imaging><PETSCAN><PETT><PSEN1><Pathology><Pathway interactions><Patients><Pericapillary Cell><Pericytes><Perivascular Cell><Phenotype><Phosphorylation><Plasmacytoma Growth Factor><Population><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Preinterleukin 1 Alpha><Preinterleukin 1 Beta><Preparation><Prevention trial><Primary Senile Degenerative Dementia><Protein Phosphorylation><Publishing><Rad.-PET><Recording of previous events><Replicative Senescence><Research><Research Resources><Resources><Role><Rouget Cells><S182 protein><SNCA><SNCA protein><SUMOylation><Sampling><Smooth Muscle Cells><Smooth Muscle Myocytes><Smooth Muscle Tissue Cell><Spillage><Statistical Data Analyses><Statistical Data Analysis><Statistical Data Interpretation><Sumoylation Pathway><Synapses><Synaptic><System><TAR DNA-binding protein 43><TDP-43><TDP43><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><TREM2><TREM2 gene><Techniques><Testing><Text><Tissue Banks><Tissue Collection><Tissue repository><Tissues><Travel><Triggering Receptor Expressed in Myeloid Cells 2><Triggering Receptor Expressed on Myeloid Cells 2><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Ubiquitilation><Ubiquitination><Ubiquitinoylation><United States National Institutes of Health><Universities><Variant><Variation><Vascular Smooth Muscle><Visit><Work><a-syn><a-synuclein><advanced age><age associated><age associated alterations><age associated changes><age associated disease><age associated disorder><age associated impairment><age correlated><age correlated alterations><age correlated changes><age dependent><age dependent alterations><age dependent changes><age dependent disease><age dependent disorder><age dependent impairment><age linked><age related><age related alterations><age related changes><age related human disease><age specific><age specific alterations><age specific changes><age-related disease><age-related disorder><age-related impairment><ages><alpha synuclein><alpha synuclein gene><alphaSP22><alterations with age><alzheimer risk><astrocytic glia><asyn><blood vessels in the brain><brain blood vessels><brain control><brain vasculature><cell type><cellular development><cellular differentiation><cerebral blood vessel><cerebral vasculature><cerebrovascular vessels><cerebrovasculature><changes with age><complex data><cytokine><disease onset><disorder onset><early onset><early onset AD><early onset Alzheimer's><experience><familial AD><familial Alzheimer><familial Alzheimer disease><genome mutation><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><geriatric><gitter cell><glial activation><glial cell activation><hiPSC><hiPSC-derived neurons><histories><human iPS><human iPSC><human iPSC-derived sensory neuron><human induced pluripotent cell><human induced pluripotent stem cells><human inducible stem cells><iPSC-derived human neuron><imaging><immunocytochemistry><induced human pluripotent stem cells><inflammation marker><inflammatory marker><interferon beta 2><loss of function><mesoglia><microglial cell><microgliocyte><microtubule bound tau><microtubule-bound tau><monogenic disease><monogenic disorder><necropsy><neural inflammation><neuroinflammation><neuroinflammatory><neuron glial antigen 2><neuronal><neuropathologic><neuropathological><neuropathology><non A-beta component of AD amyloid><non A4 component of amyloid precursor><novel><older groups><older individuals><older person><pathway><perivascular glial cell><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><postmortem><preparations><presenilin 1 protein><presenilin-1><primary degenerative dementia><programs><protein TDP-43><protein TDP43><response><scRNA-seq><senile dementia of the Alzheimer type><senior citizen><single cell RNA-seq><single cell RNAseq><single cell analysis><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><single-gene disease><single-gene disorder><social role><statistical analysis><synapse><synapse function><synaptic function><synuclein><tau><tau Proteins><tau factor><tomography><ubiquination><ubiquitin conjugation><whole genome association analysis><whole genome association studies><whole genome association study><α synuclein gene><α-syn><α-synuclein><τ Proteins>