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Principal Investigator: LIAN LI
Organization: EMORY UNIVERSITY
Fiscal Year: 2024
Award: $234,750
Funding agency: National Institute on Aging
Project Summary / Abstract
Alzheimer's disease (AD) is a devastating dementia that occurs either in rare, familial forms or in common,
sporadic forms. Current understanding of AD pathogenic mechanisms is incomplete, and amyloidocentric
clinical trials have failed to show therapeutic efficacy, highlighting the need for a better understanding of AD
pathogenic mechanisms to find new strategies of intervention. Dysregulated endosomal trafficking is
increasingly recognized as a pathological hub in AD pathogenesis, but the molecular basis of endosomal
dysfunction in AD remains unclear. Recent discovery of endosomal trafficking regulator SORL1 (sortilin-
related receptor 1, also known as SORLA or LR11) as a major risk factor for both early-onset and late-
onset AD opens up a new avenue for studying the pathogenic mechanisms that trigger endosomal
dysfunction and neurodegeneration in AD. SORL1 has emerged as the fourth gene for autosomal-
dominant familial AD, with loss-of-function SORL1 truncation mutations conferring high pathogenicity to a
similar extent as that caused by mutations in the three well-known familial AD genes: amyloid precursor
protein (APP) and presenilins 1 and 2. Furthermore, missense variants in the coding region of SORL1 gene
have been identified as a genetic risk factor for development of sporadic AD. SORL1 is a sorting receptor
in the control of cargo trafficking between endosome, trans-Golgi network (TGN), and plasma membrane.
Increasing evidence indicates that SORL1 plays a key neuroprotective role against A accumulation and
neurodegeneration by promoting APP trafficking from endosome to TGN and to cell surface, facilitating A
trafficking to lysosome for degradation, and maintaining the integrity of the endo-lysosomal system. Despite
strong evidence linking SORL1 dysfunction to AD pathogenesis, the molecular mechanisms that regulate
SORL1 function remain poorly understood. The proposed project aims to address this knowledge gap and
perform innovative research to elucidate SORL1 regulation mechanisms and their alterations in AD. The
findings and novel insights generated from this project will advance our understanding of SORL1
dysfunction and endosomal trafficking dysregulation in AD and may point to new therapeutic strategies for
AD treatment.
Terms: <AD dementia><AD3-like protein><AD3LP><Active Follow-up><Address><Age><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer risk factor><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's biomarker><Alzheimer's brain><Alzheimer's disease biological marker><Alzheimer's disease brain><Alzheimer's disease risk><Alzheimers Dementia><Alzheimer’s biological marker><Alzheimer’s disease biomarker><Amentia><Amino Acids><Amyloid A4 Protein Precursor><Amyloid Protein Precursor><Amyloid beta-Protein Precursor><Amyloid β-Protein Precursor><Area><Asparagine><Autopsy><Brain><Brain Nervous System><Cell membrane><Cell surface><Clinical Trials><Code><Coding System><Cold-Insoluble Globulins><Consensus Sequence><Cytoplasmic Domain><Cytoplasmic Membrane><Cytoplasmic Tail><Dementia><Development><Disease><Disorder><Dysfunction><EGF-Like Domain><Elderly><Encephalon><Endosomes><FN1><Fibronectin 1><Fibronectins><Frontal Temporal Dementia><Frontotemporal Dementia><Functional disorder><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genetic predisposing factor><Glycans><Glycopeptides><Glycoproteins><Human><Impairment><Intervention><Intervention Strategies><Knowledge><L-Asparagine><LDL Receptors><LETS Proteins><Large External Transformation-Sensitive Protein><Late Onset Alzheimer Disease><Link><Lipoprotein LDL Receptors><Low Density Lipoprotein Receptor><Lysosomes><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Metabolic Glycosylation><Modern Man><Modification><Molecular><Molecular Analysis><Mutation><N-Glycosylation Site><Nerve Degeneration><Neuron Degeneration><Opsonic Glycoprotein><Opsonic alpha(2)SB Glycoprotein><PSEN1><PSEN2><Paralysis Agitans><Parkinson><Parkinson Disease><Pathogenesis><Pathogenicity><Pathologic><Peptide Domain><Physiopathology><Plasma Membrane><Play><Polysaccharides><Position><Positioning Attribute><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Primary Parkinsonism><Primary Senile Degenerative Dementia><Protein Domains><Protein Modification><Protein Trafficking><Proteins><Receptor Protein><Receptosomes><Regulation><Research><Risk Factors><Role><S182 protein><Sampling><Site><Sorting><Surface Proteins><System><TM Domain><Tertiary Protein Structure><Testing><Transmembrane Domain><Transmembrane Region><Treatment Efficacy><Vacuolar Protein Sorting><Validation><Variant><Variation><active followup><advanced age><ages><alpha 2-Surface Binding Glycoprotein><alzheimer risk><aminoacid><amyloid precursor protein><autosome><biomarker development><brain tissue><case control><case-controlled><cohort><developmental><early onset><experiment><experimental research><experimental study><experiments><extracellular><familial AD><familial Alzheimer><familial Alzheimer disease><follow up><follow-up><followed up><followup><front temporal dementia><frontal lobe dementia><frontotemporal lobar dementia><frontotemporal lobe degeneration associated with dementia><genetic risk factor><genome mutation><geriatric><glycoproteomics><glycosylation><in vivo><inherited factor><innovate><innovation><innovative><insight><intervention efficacy><interventional strategy><late onset alzheimer><loss of function><loss of function mutation><mild cognitive disorder><mild cognitive impairment><necropsy><neural degeneration><neurodegeneration><neurodegenerative><neurological degeneration><neuronal degeneration><neuropathologic><neuropathological><neuropathology><neuroprotection><neuroprotective><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><pathophysiology><plasmalemma><postmortem><presenilin 1 protein><presenilin 2 protein><presenilin-1><presenilin-2><primary degenerative dementia><protein folding><protein transport><rare allele><rare mutation><rare variant><receptor><senile dementia of the Alzheimer type><senior citizen><social role><sortilin><therapeutic agent development><therapeutic development><therapeutic efficacy><therapy efficacy><trafficking><trans-Golgi Network><validations>