Summary: Aquaporin-4 could be a potential target for preventing and treating Alzheimer’s disease, a new study reports.
Source: OHSU.
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Two images compare brain scans from an older individual who had Alzheimer’s (on the left) with an older cognitively healthy individual (n the right). The red fluorescence is the membrane protein aquaporin-4. The cognitively healthy individual has relatively even aquaporin-4 expression throughout the tissue and a stark enhancement of expression around the blood vessel, whereas the individual with Alzheimer’s has uneven, “patchy” expression of aquaporin-4. Neurosciencenews image is credited to OHSU.
OHSU researchers compare prevalence of aquaporin-4 in the brains of those who had Alzheimer’s to those who didn’t have the disease.
A new scientific discovery may provide a future avenue for treatment and prevention of Alzheimer’s disease.
A study published Nov. 28 in the journal JAMA Neurology examined aquaporin-4, a type of membrane protein in the brain. Using brains donated for scientific research, researchers at OHSU discovered a correlation between the prevalence of aquaporin-4 among older people who did not suffer from Alzheimer’s as compared to those who had the disease.
“It suggests that aquaporin-4 might be a useful target in preventing and treating Alzheimer’s disease,” said senior author Jeffrey Iliff, Ph.D., an Assistant Professor in the Department of Anesthesiology and Perioperative Medicine in the OHSU School of Medicine. “However, we aren’t under any illusion that if we could just fix this one thing, then we’d be able to cure Alzheimer’s Disease.”
Alzheimer’s is a progressive disease, most often associated with aging, that causes problems with memory, thinking and behavior. It is the leading cause of dementia worldwide and is currently the sixth leading cause of death in the United States. The disease has no known cure but there are treatments available for some of its symptoms.
Aquaporin-4 is a key part of a brain-wide network of channels, collectively known as the glymphatic system, that permits cerebral-spinal fluid from outside the brain to wash away proteins such as amyloid and tau that build up within the brain. These proteins tend to accumulate in the brains of some people suffering from Alzheimer’s, which may play a role in destroying nerve cells in the brain over time.
“This system, and the failure of the system, may be one of many things that goes wrong in people with Alzheimer’s disease,” Iliff said.
The study closely examined 79 brains donated through the Oregon Brain Bank, a part of the OHSU Layton Aging and Alzheimer’s Disease Center. They were separated into three groups: People younger than 60 without a history of neurological disease; people older than 60 with a history of Alzheimer’s; and people older than 60 without Alzheimer’s.
Researchers found that in the brains of younger people and older people without Alzheimer’s, the aquaporin-4 protein was well organized, lining the blood vessels of the brain. However within the brains of people with Alzheimer’s, the aquaporin-4 protein appeared disorganized, which may reflect an inability of these brains to efficiently clear away wastes like amyloid beta. The study concluded that future research focusing on aquaporin-4 – either through its form or function – may ultimately lead to medication to treat or prevent Alzheimer’s disease.
In 2015, a multidisciplinary team of scientists from OHSU led by Iliff was awarded a $1.4 million grant from the Paul G. Allen Family Foundation to use to develop new imaging techniques based on MRI to see these processes at work in the aging human brain for the first time.
In addition to Iliff, co-authors included Douglas M. Zeppenfeld; Matthew Simon, J. Douglas Haswell, and Daryl D’Abreo of the OHSU Department of Anesthesiology and Perioperative Medicine; Charles Murchison, Joseph F. Quinn, M.D., and Jeffrey Kaye, M.D., of the OHSU Department of Neurology; and Marjorie R. Grafe, M.D., Ph.D., and Randall L. Woltjer, M.D., Ph.D., of the Department of Pathology.
Funding: This work was supported by funding from the American Heart Association, grant 12SDG11820014, the Oregon Partnership for Alzheimer’s Research, grants from the Research and Development Office of the Department of Veterans Affairs and the National Institutes of Health (NS089709), including Alzheimer’s Disease Center grant AG08017 from the National Institute on Aging that supported the longitudinal follow-up and subsequent brain autopsies providing the human brain samples used in this study.
Source: Erik Robinson – OHSU
Image Source: This NeuroscienceNews.com image is credited to OHSU.
Original Research: Full open access research for “Association of Perivascular Localization of Aquaporin-4 With Cognition and Alzheimer Disease in Aging Brains” by Douglas M. Zeppenfeld, BS; Matthew Simon, BS1; J. Douglas Haswell, BS1; Daryl D’Abreo1; Charles Murchison, MS; Joseph F. Quinn, MD; Marjorie R. Grafe, MD, PhD; Randall L. Woltjer, MD, PhD; Jeffrey Kaye, MD; and Jeffrey J. Iliff, PhD in JAMA Neurology. Published online November 28 2016 doi:10.1001/jamaneurol.2016.4370
Abstract
Association of Perivascular Localization of Aquaporin-4 With Cognition and Alzheimer Disease in Aging Brains
Importance Cognitive impairment and dementia, including Alzheimer disease (AD), are common within the aging population, yet the factors that render the aging brain vulnerable to these processes are unknown. Perivascular localization of aquaporin-4 (AQP4) facilitates the clearance of interstitial solutes, including amyloid-β, through the brainwide network of perivascular pathways termed the glymphatic system, which may be compromised in the aging brain.
Objectives To determine whether alterations in AQP4 expression or loss of perivascular AQP4 localization are features of the aging human brain and to define their association with AD pathology.
Design, Setting, and Participants Expression of AQP4 was analyzed in postmortem frontal cortex of cognitively healthy and histopathologically confirmed individuals with AD by Western blot or immunofluorescence for AQP4, amyloid-β 1-42, and glial fibrillary acidic protein. Postmortem tissue and clinical data were provided by the Oregon Health and Science University Layton Aging and Alzheimer Disease Center and Oregon Brain Bank. Postmortem tissue from 79 individuals was evaluated, including cognitively intact “young” individuals aged younger than 60 years (range, 33-57 years), cognitively intact “aged” individuals aged older than 60 years (range, 61-96 years) with no known neurological disease, and individuals older than 60 years (range, 61-105 years) of age with a clinical history of AD confirmed by histopathological evaluation. Forty-eight patient samples (10 young, 20 aged, and 18 with AD) underwent histological analysis. Sixty patient samples underwent Western blot analysis (15 young, 24 aged, and 21 with AD).
Main Outcomes and Measures Expression of AQP4 protein, AQP4 immunoreactivity, and perivascular AQP4 localization in the frontal cortex were evaluated.
Results Expression of AQP4 was associated with advancing age among all individuals (R2 = 0.17; P = .003). Perivascular AQP4 localization was significantly associated with AD status independent of age (OR, 11.7 per 10% increase in localization; z = −2.89; P = .004) and was preserved among eldest individuals older than 85 years of age who remained cognitively intact. When controlling for age, loss of perivascular AQP4 localization was associated with increased amyloid-β burden (R2 = 0.15; P = .003) and increasing Braak stage (R2 = 0.14; P = .006).
Conclusions and Relevance In this study, altered AQP4 expression was associated with aging brains. Loss of perivascular AQP4 localization may be a factor that renders the aging brain vulnerable to the misaggregation of proteins, such as amyloid-β, in neurodegenerative conditions such as AD.
“Association of Perivascular Localization of Aquaporin-4 With Cognition and Alzheimer Disease in Aging Brains” by Douglas M. Zeppenfeld, BS; Matthew Simon, BS1; J. Douglas Haswell, BS1; Daryl D’Abreo1; Charles Murchison, MS; Joseph F. Quinn, MD; Marjorie R. Grafe, MD, PhD; Randall L. Woltjer, MD, PhD; Jeffrey Kaye, MD; and Jeffrey J. Iliff, PhD in JAMA Neurology. Published online November 28 2016 doi:10.1001/jamaneurol.2016.4370
http://neurosciencenews.com/aquaporin-4-alzheimers-5647/
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