All neurodegenerative diseases, including Alzheimer's disease (AD) are associated with the accumulation of misfolded protein aggregates. The brain lacks the lymphatic drainage system that peripheral tissues rely on for macroscopic waste removal;however we recently discovered a brain-wide system that subserves this role. We named it the 'glymphatic'pathway, because it is dependent on aquaporin 4 (AQP4) water channels expressed in a highly polarized pattern on astroglial processes surrounding blood vessels. As much as 60% of soluble A? proteins are cleared from the interstitial space along the glymphatic pathway and clearance is sharply reduced in a murine AD model [expressing mutant human amyloid precursor protein (APPsw) and presenilin 1(PS E9)] when compared to age-matched wildtype mice. The proposed studies will utilize the first rodent AD model-transgenic APPsw/PS E9 rats-that replicates all the hallmarks of AD in humans, including amylodosis, reactive astro- and microgliosis, and progressive neuronal loss. HYPOTHESES: (1) Dysfunction of the glymphatic system in young, middle aged and old rats caused by oxidative stress and mislocation of AQP4 contributes to vascular amyloid deposition in APPsw/PS E9 rats. (2) Glymphatic transport can be quantified brain-wide using clinically relevant magnetic resonance imaging (MRI) in live rodents by minimally invasive lumbar administration of contrast agents. (3) Young (6 months) and middle-aged (16 months) APPsw/PS E9 rats that by MRI imaging are identified as those that exhibit the most severe decline in glymphatic clearance are at higher risk of developing AD pathology, detected as cognitive decline, and oxidative stress and amyloidosis, when they reach old age (26 months).
Aim 1 : Using CSF tracers and optical imaging, we will correlate glymphatic decline locally with the severity oxidative stress, astro- an microgliosis, loss of polarized perivascular AQP4, amyloid burden, and neuronal loss as a function of age in APPsw/PS E9 and wildtype rats.
Aim 2 : Establish a clinically relevant rodent imaging platform for evaluation of glymphatic pathway function using minimally invasive techniques using clinically relevant magnetic resonance imaging (MRI) combined with minimally invasive administration of paramagnetic contrast via lumbar intrathecal space.
Aim 3 : Using the glymphatic diagnostic MRI test developed in Aim 2, we will test the hypothesis that glymphatic pathway dysfunction in 6 and 16 months old APPsw/PS E9 rats predicts the severity of cognitive decline and amyloid burden in the same rats at 26 months. These studies will take advantage of the known interanimal variability of disease progression in APPsw/PS E9 rats to define whether failure of glymphatic function contributes to AD pathology. These studies present the first attempt to apply MRI imaging to track glymphatic dysfunction in normal aging and in AD. Clinical translation of the MRI imaging platform may allow similar questions to be asked in humans and permit tracking of interventional therapeutic approaches intended to slow AD progression.

Public Health Relevance

This project will test the hypothesis that age-related decline in glymphatic clearance precedes and contributes to cognitive decline and amyloidosis in wild type rats and in a transgenic rat model of Alzheimer disease. The project will take advantage of the complementary expertise of two laboratories (MRI and optical imaging) that have successfully collaborated in the past.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG048769-01
Application #
8791832
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Petanceska, Suzana
Project Start
2014-09-01
Project End
2019-05-31
Budget Start
2014-09-01
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Rochester
Department
Neurology
Type
School of Medicine & Dentistry
DUNS #
City
Rochester
State
NY
Country
United States
Zip Code
14627
Smith, Nathan A; Kress, Benjamin T; Lu, Yuan et al. (2018) Fluorescent Ca2+ indicators directly inhibit the Na,K-ATPase and disrupt cellular functions. Sci Signal 11:
Verkhratsky, Alexei; Nedergaard, Maiken (2018) Physiology of Astroglia. Physiol Rev 98:239-389
Lundgaard, Iben; Wang, Wei; Eberhardt, Allison et al. (2018) Beneficial effects of low alcohol exposure, but adverse effects of high alcohol intake on glymphatic function. Sci Rep 8:2246
Rasmussen, Martin Kaag; Mestre, Humberto; Nedergaard, Maiken (2018) The glymphatic pathway in neurological disorders. Lancet Neurol 17:1016-1024
Benveniste, Helene; Liu, Xiaodan; Koundal, Sunil et al. (2018) The Glymphatic System and Waste Clearance with Brain Aging: A Review. Gerontology :1-14
Mestre, Humberto; Hablitz, Lauren M; Xavier, Anna Lr et al. (2018) Aquaporin-4-dependent glymphatic solute transport in the rodent brain. Elife 7:
Plog, Benjamin A; Nedergaard, Maiken (2018) The Glymphatic System in Central Nervous System Health and Disease: Past, Present, and Future. Annu Rev Pathol 13:379-394
Plog, Benjamin A; Mestre, Humberto; Olveda, Genaro E et al. (2018) Transcranial optical imaging reveals a pathway for optimizing the delivery of immunotherapeutics to the brain. JCI Insight 3:
von Holstein-Rathlou, Stephanie; Petersen, Nicolas Caesar; Nedergaard, Maiken (2018) Voluntary running enhances glymphatic influx in awake behaving, young mice. Neurosci Lett 662:253-258
Lee, Hedok; Mortensen, Kristian; Sanggaard, Simon et al. (2018) Quantitative Gd-DOTA uptake from cerebrospinal fluid into rat brain using 3D VFA-SPGR at 9.4T. Magn Reson Med 79:1568-1578

Showing the most recent 10 out of 66 publications