Determining if Reduced Insulin Response in the Brain is Linked to Cognitive Loss
Determining if Reduced Insulin Response in the Brain is Linked to Cognitive Loss
批准号:
9188283
负责人:
THOMAS A JONGENS
金额:
$23.8万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-09-01 至 2018-04-30
关键词:
AdultAffectAgeAge of OnsetAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAutopsyBrainCatalytic DomainCerebral cortexCleaved cellClinical ResearchCognitionCognitiveCognitive deficitsComplexCourtshipDefectDementiaDevelopmentDiabetes MellitusDiagnosisDietDrosophila genusElderlyGenesGeneticGoalsHippocampus (Brain)HumanImpaired cognitionIndividualInsulinInsulin ReceptorInsulin ResistanceInsulin Signaling PathwayInvestigationLeadLearningLinkMaintenanceMemoryMemory LossMemory impairmentMetabolicModelingMusMutationNon-Insulin-Dependent Diabetes MellitusPTEN genePathway interactionsPatientsPeptide HydrolasesPeripheralPhosphatidylinositolsPhosphotransferasesPlayReducing dietRegulationRiskRisk FactorsRoleShort-Term MemorySliceTestingTimeTrainingVascular Cognitive Impairmentage relatedfamilial Alzheimer diseaseflygene functioninsulin signalingloss of functionloss of function mutationmind controlmutantnotch proteinnovel therapeutic interventionpresenilinpreventreceptorreceptor downregulationreceptor expressionresponsesecretase
中文摘要
项目总结
英文摘要
Project Summary
As people age, their risk for developing dementia increases. This risk is enhanced for those with type II
diabetes. In fact, individuals with type II diabetes are more than twice as likely to suffer from dementia, either
through the development of Alzheimers disease (AD), Vascular cognitive impairment (CVI) or dementia in
general. Examination of brains from AD patients also reveals this correlation as most brains from AD patients
display insulin resistance in the hippocampus, even in patients that have not been clinically diagnoses with
type II diabetes. This brain form of insulin resistance is referred to as type III diabetes.
In previous studies we examined the effect of reduced presenilin activity utilizing known loss of function
mutations of Drosophila presenilin (psn). We found that flies with reduced psn activity (psn-hets) displayed an
age-onset loss-of-learning and memory in the classic courtship learning and memory paradigm. In more recent
studies of the psn-het brains we have found that they develop brain insulin resistance with age. We find that
when the psn-het flies are young (day 5 of adulthood) and display normal cognition, their brains display
increased insulin signaling and increased sensitivity to insulin stimulation. Old psn-het brains (day 30 of
adulthood) that display loss of learning and memory fail to respond to insulin stimulation. We hypothesize that
the establishment of insulin resistance in the brains of the old psn-hets causes the cognitive deficits displayed
by this model. In the first aim of this proposal we will determine if psn mutations linked to familial Alzheimers
disease (FAD) also lead to altered insulin signaling in the brain, brain insulin resistance and age onset
cognitive loss. We will then explore if the reduction of insulin signaling in the brain can rescue the formation of
brain insulin resistance and cognitive loss. In the second aim of this proposal we will determine if psn
mutations lead to alterations in peripheral insulin signaling and peripheral insulin resistance. These studies will
determine if loss or alteration of psn activity preferentially induce insulin resistance in the brain. We will also
test if treatments that are known to induce the development of peripheral insulin resistance in flies also cause
brain insulin-resistance and cognitive deficits. These studies will be performed with control flies, psn-hets and
flies heterozygous for FAD mutations, allowing for an examination of the interaction of diet and reduced psn
activity. These studies will explore the role that reduction of, or alteration in psn activity has on insulin signaling
and the establishment of insulin resistance in the brain and whether this can cause cognitive impairment.
These studies will also provide a useful model to explore the dementia due to the development of brain insulin
resistance in general.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Mitochondrial dysfunction in Fragile X: Mechanisms and treatments
-
批准号:10735521
-
项目类别:
-
资助金额:$53.98万
-
财政年份:2023
-
负责人:THOMAS A JONGENS
-
依托单位:
Determining whether metabolic and mitochondrial pathophysiology are a common feature of three distinct genetic models of ASD
-
批准号:10373378
-
项目类别:
-
资助金额:$24.0万
-
财政年份:2021
-
负责人:THOMAS A JONGENS
-
依托单位:
Determining whether metabolic and mitochondrial pathophysiology are a common feature of three distinct genetic models of ASD
-
批准号:10533812
-
项目类别:
-
资助金额:$19.93万
-
财政年份:2021
-
负责人:THOMAS A JONGENS
-
依托单位:
Investigating a positive biological role for the A Beta peptide
-
批准号:9809520
-
项目类别:
-
资助金额:$24.3万
-
财政年份:2019
-
负责人:THOMAS A JONGENS
-
依托单位:
Regulation of the Drosophila Fragile X Protein by siRNA Pathway Components
-
批准号:7904143
-
项目类别:
-
资助金额:$19.52万
-
财政年份:2009
-
负责人:THOMAS A JONGENS
-
依托单位:
Regulation of the Drosophila Fragile X Protein by siRNA Pathway Components
-
批准号:7706262
-
项目类别:
-
资助金额:$23.61万
-
财政年份:2009
-
负责人:THOMAS A JONGENS
-
依托单位:
Modeling Fragile X Syndrome in Drosophilia
-
批准号:8225215
-
项目类别:
-
资助金额:$34.15万
-
财政年份:2004
-
负责人:THOMAS A JONGENS
-
依托单位:
Modeling Fragile X Syndrome in Drosophila
-
批准号:7231962
-
项目类别:
-
资助金额:$31.28万
-
财政年份:2004
-
负责人:THOMAS A JONGENS
-
依托单位:
Modeling Fragile X Syndrome in Drosophila
-
批准号:7062468
-
项目类别:
-
资助金额:$32.21万
-
财政年份:2004
-
负责人:THOMAS A JONGENS
-
依托单位:
Modeling Fragile X Syndrome in Drosophila
-
批准号:6949152
-
项目类别:
-
资助金额:$32.99万
-
财政年份:2004
-
负责人:THOMAS A JONGENS
-
依托单位:
Modeling Fragile X Syndrome in Drosophila
-
批准号:6869782
-
项目类别:
-
资助金额:$32.99万
-
财政年份:2004
-
负责人:THOMAS A JONGENS
-
依托单位:
Modeling Fragile X Syndrome in Drosophilia
-
批准号:8410097
-
项目类别:
-
资助金额:$32.92万
-
财政年份:2004
-
负责人:THOMAS A JONGENS
-
依托单位:
Modeling Fragile X Syndrome in Drosophilia
-
批准号:7790102
-
项目类别:
-
资助金额:$34.5万
-
财政年份:2004
-
负责人:THOMAS A JONGENS
-
依托单位:
Modeling Fragile X Syndrome in Drosophilia
-
批准号:8019507
-
项目类别:
-
资助金额:$34.2万
-
财政年份:2004
-
负责人:THOMAS A JONGENS
-
依托单位:
ESTABLISHMENT OF THE GERM CELL LINEAGE IN DROSOPHILA
-
批准号:6520981
-
项目类别:
-
资助金额:$24.56万
-
财政年份:1997
-
负责人:THOMAS A JONGENS
-
依托单位:
ESTABLISHMENT OF THE GERM CELL LINEAGE IN DROSOPHILA
-
批准号:6725355
-
项目类别:
-
资助金额:$24.53万
-
财政年份:1997
-
负责人:THOMAS A JONGENS
-
依托单位:
ESTABLISHMENT OF THE GERM CELL LINEAGE IN DROSOPHILA
-
批准号:2025783
-
项目类别:
-
资助金额:$19.84万
-
财政年份:1997
-
负责人:THOMAS A JONGENS
-
依托单位:
ESTABLISHMENT OF THE GERM CELL LINEAGE IN DROSOPHILA
-
批准号:6863688
-
项目类别:
-
资助金额:$24.52万
-
财政年份:1997
-
负责人:THOMAS A JONGENS
-
依托单位:
ESTABLISHMENT OF THE GERM CELL LINEAGE IN DROSOPHILA
-
批准号:6636916
-
项目类别:
-
资助金额:$24.54万
-
财政年份:1997
-
负责人:THOMAS A JONGENS
-
依托单位:
ESTABLISHMENT OF THE GERM CELL LINEAGE IN DROSOPHILA
-
批准号:2889229
-
项目类别:
-
资助金额:$21.82万
-
财政年份:1997
-
负责人:THOMAS A JONGENS
-
依托单位:
海外基金