Amyloid-p (AP) peptide accumulation and aggregation are initiating events in the pathogenesis of Alzheimer's disease (AD). AB aggregation is concentration-dependent and can result from its overproduction, inefficient clearance, or both. LRP1 is a multifunctional lipoprotein receptor that modulates both AB production and clearance. While the fast endocytosis of LRP1 modulates the endocytosis and processing of amyloid precursor protein (APP) to influence AB production, the endocytic functions of both LRP1 and cell surface heparan sulfate proteoglycan (HSPG) facilitate cellular uptake and clearance of Ap. A major goal of this project is to examine the in vivo roles of LRP1 and HSPG in brain AP production and clearance in mice with altered gene expression by viral mediated or genetic approaches. Our recent collaborative work with the groups of David Holtzman and John Cirrito has also showed that synaptic activity regulates APP processing to AB, and that this regulation requires the endocytosis of APP. In addition to presynaptic mechanisms, AP producfion can also be regulated by a postsynaptic mechanism that involves NMDARs, which interact with LRP1. Therefore, we plan to determine whether LRP1/HSPGmediated Ap production or clearance is regulated by synaptic activity. Our overall hypothesis is that LRP1 and HSPG play critical roles in synaptic-dependent regulation of both AB production and clearance, and that dysregulation of these pathways leads to AP accumulation and aggregation in AD brains. To test our hypothesis, we will collaborate with Drs. David Holtzman and John Cirrito, who have extensive experience in modulating synaptic activity and measuring AB metabolism in vivo, to pursue three specific aims.
In Aim 1, we will dissect the role of LRP1 in synaptic-dependent AB generation in vivo.
In Aim 2, we will dissect the role of LRP1 and HSPG in synaptic-dependent AB clearance in vivo.
In Aim 3, we will examine the specific roles of LRPI and HSPG in neurons and astrocytes in AB metabolism and amyloid pathology in vivo using conditional knockout mice. Together, these studies should allow us to dissect the molecular mechanisms underlying synaptic regulation of brain AP metabolism and may define novel targets for AD therapy.

Public Health Relevance

AD is the leading cause of dementia in elderly. Mounting evidence indicates that AB accumulation and aggregation in the brain are central and early events in AD pathogenesis. The major goal of our project is to dissect molecular pathways that mediate AB production and clearance, and examine how these AP metabolic events are regulated by brain synaptic activity. Our studies should define AB metabolic pathways at the molecular and synaptic levels and should identify novel diagnostic and therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS074969-03
Application #
8642682
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
3
Fiscal Year
2014
Total Cost
$293,199
Indirect Cost
$50,625
Name
Washington University
Department
Type
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Liu, Chia-Chen; Zhao, Na; Yamaguchi, Yu et al. (2016) Neuronal heparan sulfates promote amyloid pathology by modulating brain amyloid-β clearance and aggregation in Alzheimer's disease. Sci Transl Med 8:332ra44
Fisher, Jonathan R; Wallace, Clare E; Tripoli, Danielle L et al. (2016) Redundant Gs-coupled serotonin receptors regulate amyloid-β metabolism in vivo. Mol Neurodegener 11:45
Yamazaki, Yu; Baker, Darren J; Tachibana, Masaya et al. (2016) Vascular Cell Senescence Contributes to Blood-Brain Barrier Breakdown. Stroke 47:1068-77
Tachibana, Masaya; Shinohara, Mitsuru; Yamazaki, Yu et al. (2016) Rescuing effects of RXR agonist bexarotene on aging-related synapse loss depend on neuronal LRP1. Exp Neurol 277:1-9
Shinohara, Mitsuru; Kanekiyo, Takahisa; Yang, Longyu et al. (2016) APOE2 eases cognitive decline during Aging: Clinical and preclinical evaluations. Ann Neurol :
Sakae, Nobutaka; Liu, Chia-Chen; Shinohara, Mitsuru et al. (2016) ABCA7 Deficiency Accelerates Amyloid-β Generation and Alzheimer's Neuronal Pathology. J Neurosci 36:3848-59
Yuede, Carla M; Lee, Hyo; Restivo, Jessica L et al. (2016) Rapid in vivo measurement of β-amyloid reveals biphasic clearance kinetics in an Alzheimer's mouse model. J Exp Med 213:677-85
Ju, Yo-El S; Finn, Mary Beth; Sutphen, Courtney L et al. (2016) Obstructive sleep apnea decreases central nervous system-derived proteins in the cerebrospinal fluid. Ann Neurol 80:154-9
Shinohara, Mitsuru; Murray, Melissa E; Frank, Ryan D et al. (2016) Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer's disease. Acta Neuropathol 132:225-34
Fu, Yuan; Zhao, Jing; Atagi, Yuka et al. (2016) Apolipoprotein E lipoprotein particles inhibit amyloid-β uptake through cell surface heparan sulphate proteoglycan. Mol Neurodegener 11:37

Showing the most recent 10 out of 59 publications