APOE genotype is the strongest genetic risk factor for Alzheimer's disease (AD); the ?4 allele increases risk in a dose-dependent fashion and the ?2 allele decreases risk. APOE appears to influence AD at least in part via isoform-specific effects of apoE on A? clearance and aggregation; however, there are likely additional mechanisms by which apoE influences AD. Interactions between apoE and tau, whose aggregation is linked with neurodegeneration, may be an important mechanism as to how apoE influences AD. Certain forms of apoE can bind to tau in an isoform-specific fashion and tau pathology is increased in the brain of ?4 carriers with AD. We have preliminary data validating a recent paper which shows that a mouse model of tauopathy, (P301S), develops significantly more tauopathy in the absence of apoE. Data from many labs including our own strongly suggests that an important mechanism in tau pathogenesis in tauopathies including AD is that aggregated forms of tau escape the cytoplasm and spread to both adjacent and synaptically connected cells to induce transcellular seeding of tau and disease progression. Tau is present in the interstitial fluid space of the brain normally and this is likely also the case for tau aggregates. Since apoE is an abundantly secreted protein from glial cells, can bind to tau, and both apoE and tau aggregates strongly bind to HSPGs, we hypothesize that apoE interacts with tau in the brain extracellular space to influence its metabolism, aggregation, and effects on neurodegeneration. Our primary hypothesis is that human APOE isoforms dose-dependently influences tau pathology both directly as well as via effects on A?. Our secondary hypothesis is that human apoE-containing lipoproteins bind to extracellular tau aggregates and influence their ability to induce tau seeding/spreading.
The specific aims are: 1) To determine the effect of human APOE isoforms on tau pathology in the presence and absence of human A?. 2) To determine the effects of human APOE isoforms on the mouse models in Aim 1 on brain interstitial fluid (ISF) tau by microdialysis as well as tau seeding activity in ISF, CSF, and brain lysates. 3) To assess the binding of apoE-containing lipoproteins to both monomeric and aggregated tau and assess their effect on cellular binding, uptake, and tau seeding activity

Public Health Relevance

Alzheimer's disease is a major public health problem with no treatments that delay, slow, or prevent the disease. We are trying to better understand mechanisms underlying how the most important genetic risk factor for Alzheimer's disease, APOE, is causing its effects. This could lead to novel insights into new treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS090934-20
Application #
8881363
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Corriveau, Roderick A
Project Start
1996-09-01
Project End
2019-07-31
Budget Start
2015-08-01
Budget End
2016-07-31
Support Year
20
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Huynh, Tien-Phat V; Davis, Albert A; Ulrich, Jason D et al. (2017) Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-? and other amyloidogenic proteins. J Lipid Res 58:824-836
Leyns, Cheryl E G; Holtzman, David M (2017) Glial contributions to neurodegeneration in tauopathies. Mol Neurodegener 12:50
Huynh, Tien-Phat V; Liao, Fan; Francis, Caroline M et al. (2017) Age-Dependent Effects of apoE Reduction Using Antisense Oligonucleotides in a Model of ?-amyloidosis. Neuron 96:1013-1023.e4
Shi, Yang; Yamada, Kaoru; Liddelow, Shane Antony et al. (2017) ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549:523-527
Chung, Won-Suk; Verghese, Philip B; Chakraborty, Chandrani et al. (2016) Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes. Proc Natl Acad Sci U S A 113:10186-91
Tambini, Marc D; Pera, Marta; Kanter, Ellen et al. (2016) ApoE4 upregulates the activity of mitochondria-associated ER membranes. EMBO Rep 17:27-36
Achariyar, Thiyagaragan M; Li, Baoman; Peng, Weiguo et al. (2016) Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation. Mol Neurodegener 11:74
Han, Byung Hee; Zhou, Meng-Liang; Johnson, Andrew W et al. (2015) Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg2576 mice. Proc Natl Acad Sci U S A 112:E881-90
Musiek, Erik S; Holtzman, David M (2015) Three dimensions of the amyloid hypothesis: time, space and 'wingmen'. Nat Neurosci 18:800-6
Yan, Ping; Zhu, Alec; Liao, Fan et al. (2015) Minocycline reduces spontaneous hemorrhage in mouse models of cerebral amyloid angiopathy. Stroke 46:1633-1640

Showing the most recent 10 out of 12 publications