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Neurology Today:
doi: 10.1097/01.NT.0000412344.31134.2b
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New Data on the Role of Hypoxia in Alzheimer Disease

Valeo, Tom

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Two new papers support the hypothesis that a decline in blood-oxygen levels somehow promotes the pathology of Alzheimer disease.

DR. HENRIK ZETTERBER...
DR. HENRIK ZETTERBER...
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In the first, researchers in Sweden reported a massive surge in amyloid beta (Abeta) production in people who suffer cardiac arrest, implicating hypoxia as a promoter of Alzheimer disease (AD). And in the other, a team of investigators in Finland found that an increase in a blood metabolite upregulated by hypoxia identifies which patients with mild cognitive impairment (MCI) are more likely to develop AD.

The Swedish researchers, reporting their results in the Dec. 14 online edition of Public Library of Science One (PLoS ONE), used a new technology known as single molecular arrays to measure changes in Abeta-42 concentrations in 25 resuscitated patients ranging in age from 25 to 85 who had experienced severe hypoxia following cardiac arrest. After 10 or more hours, Abeta-42 elevations were observed in all patients, ranging from an 80 percent increase to more than 70 times normal levels, with most in the range of three to ten times normal levels. (The average increase was about seven times greater than normal.)

“The magnitude of the increase correlated with clinical outcome,” the authors reported. “These data provide the first direct evidence in living humans that ischemia acutely increases Aß [Abeta] levels in blood. The results point to the possibility that hypoxia may play a role in the amyloidogenic process of AD.”

The authors acknowledged that the lack of a control group constitutes a limitation of the study, but pointed to a 2010 study in the International Journal of Alzheimer's Disease that found very low variability in day-to-day levels of Abeta-42 in healthy people, suggesting that the elevations found in survivors of cardiac arrest are indeed extraordinary.

The study authors noted that there are differences between acute hypoxia due to cardiac arrest and the gradual increase in hypoxia due to atherosclerosis, congestive heart failure, and other age-related reductions in blood flow. But lead author Henrik Zetterberg, MD, PhD, a research scientist in the department of psychiatry and neurochemistry at Sahlgrenska Academy at the University of Gothenburg, told Neurology Today that acute hypoxia from cardiac arrest merely accelerates the brain changes that result from other forms of hypoxia, much like administering a large dose of carcinogen to a rodent presumably accelerates the effect on tissues that would be seen in a human subjected to much smaller doses over many years.

To test this assumption, Dr. Zetterberg and colleagues plan to examine participants in the Swedish championship “static apnea” contest in March. Participants compete to hold their breath underwater as long as possible. “If the ethics committee allows us, we will sample participants during the competition,” Dr. Zetterberg said. “This is merely an attempt to look at the relationship between hypoxia and Abeta homeostasis in another context not as dramatic as cardiac arrest, and probably involving less general tissue damage and organ failure than what resuscitated cardiac arrest patients experience.”

Dr. Zetterberg also contends his findings would apply to hypoxia caused by stroke. “Animal studies suggest that Abeta accumulates in the vicinity of infarcted brain regions,” said Dr. Zetterberg. “One way to inhibit this may be to treat such patients with gamma or beta-secretase inhibitors to prevent Abeta from being produced from amyloid precursor protein.”

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EXPERTS COMMENT: PLoS ONE STUDY

Kristine Yaffe, MD, professor of psychiatry, neurology, and epidemiology at the University of California, San Francisco, who was not involved with the study, called the PLoS ONE paper “very provocative,” but noted that it probably raises more questions than it answers. Dr. Yaffe authored a study, published last August in the Journal of the American Medical Association, that linked hypoxia caused by sleep apnea to progression to AD rather than sleep fragmentation or lack of total sleep. (See the Sept. 1 Neurology Today article, http://bit.ly/qDckMV.)

“I think this paper is the first to show that peripheral amyloid goes up after hypoxia, and that's interesting because we don't really know what amyloid does normally,” Dr. Yaffe told Neurology Today. “We know that deposition in the brain leads to Alzheimer's and to changes in CSF. We know that Abeta 42 aggregates and is toxic, but we don't know much about the normal function of amyloid.”

Frank M. LaFerla, PhD, Chancellor's Professor, Neurobiology and Behavior at the University of California, Irvine, who also was not involved with the study, described the paper as “excellent.”

Dr. LaFerla, who is also director of the Institute for Memory Impairments and Neurological Disorders (MIND), said: “It demonstrates the link between oxygen levels and the production of Abeta, and supports the work we described in the 3xTg-AD mice in which we induced oligemia in the brain and observed long-term changes. I don't think there are any shortcomings in the work. It is fantastic.”

Dr. LaFerla and colleagues induced hypoperfusion in aged 3xTg-AD mice and found that global ischemia did not increase levels of Abeta. However, as he and colleagues reported in Neuroscience Letters in 2011, the injury did increase phosphorylation of the amyloid precursor protein (APP) in both the 3xTg-AD mice and wild-type controls. “Furthermore, we found an increase in insoluble total tau three months post-injury,” he and co-authors reported. “Together these findings further elucidate the long-term impact of cerebral hypoperfusion on Alzheimer's disease.”

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MCI TO AD: A LINK TO HYPOXIA?

Does hypoxia play a role in the progression of MCI to AD? Researchers at the VTT Technical Research Centre of Finland think it does. They studied metabolites in 143 people with MCI, 47 with AD, and 46 health controls, in an effort to detect which ones might signal progression from MCI to AD.

During a follow-up period ranging from one to nearly four years, 52 of the 143 MCI cases transitioned to AD, according to the report in the Dec. 13 online edition of Translational Psychiatry. A biochemical signature consisting of three metabolites was found to correlate with the transition. Of the three, the strongest predictor was 2,4-dihydroxybutanoic acid, a major component of CSF that has been found to be overproduced under low oxygen conditions.

The authors believe this molecular signature may be reliable enough to include in a neurocognitive assessment of MCI patients.

DR. MATEJ ORESIC I w...
DR. MATEJ ORESIC I w...
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“I would say our biomarker would be a useful screen which, together with neurocognitive assessment, could identify the patients in need of further and more detailed (and expensive) follow-up, such as medical imaging,” lead author Matej Oresic, PhD, a research professor, told Neurology Today in an e-mail. “But there is actually very little known about the biochemistry of 2,4-dihydroxybutanoic acid except that it is overproduced in hypoxic conditions, so more research is needed to better understand our biochemical marker in order to link it mechanistically with the pathophysiology of Alzheimer's disease.”

How does hypoxia promote AD? Weidong Le, MD, PhD, now at Baylor College of Medicine in Houston, contends that hypoxia may alter the Abeta metabolic pathway, leading to overproduction, a finding he reported in 2009 in the Neurobiology of Aging. In their own study of the relationship between hypoxia and dementia, Dr. Le and his colleagues subjected transgenic mice to chronic hypoxia for up to 10 months, which resulted in elevated levels of Abeta-42 and other metabolic abnormalities, including changes in synapsin, a protein involved in neurotransmitter release. “We also saw microglia astrocytes activated,” Dr. Le told Neurology Today. “This suggests that chronic hypoxia has a profound and long-lasting effect on the pathology relevant to Alzheimer's disease, and I think many aging people have low-level hypoxia.”

“Alternatively, cardiac arrest may cause a breakdown in the blood-brain barrier,” he said, “or act on the artery wall, which contains both aggregated and unaggregated Aßβ42. This could lead to the release of Aßβ42 into the blood stream.”

While he praised the papers by the Swedish and Finnish researchers, “this is just the tip of the iceberg,” Dr. Le said. “This is just starting to allow us to look at this area. I think another big question is, what can you do about hypoxia? Can you prevent hypoxia? If so, can you reduce the incidence of Alzheimer disease? That's another area entirely.” •

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REFERENCES:

• Zetterberg H, Mörtberg E. Song L, Blennow K, et al. Hypoxia due to cardiac Arrest Induces a Time-Dependent Increase in Serum Amyloid b Levels in Humans. PLoS One 2011;6(12):e28263;E-pub 2011 Dec. 14

• Orešič M, Hyötyläinen T, Soininen H, et al. Metabolome in progression to Alzheimer's disease. Translational Psychiatry 2011;1, e57; E-pub 2011 Dec. 13.

• Yaffe K, Laffan AM, Harrison SL, Redline S, Spira AP, Ensrud KE, Ancoli-Israel S, Stone KL. Sleep-disordered breathing, hypoxia, and risk of mild cognitive impairment and dementia in older women. JAMA 2011;306(6):613-619.

• Wang Z, Yang D, Zhang X, Li T, Li J, Tang Y, Le W. Hypoxia-induced down-regulation of neprilysin by histone modification in mouse primary cortical and hippocampal neurons. PLoS One 2011;6(4):e19229.

• Le W et al. Hypoxia increases Aß generation by altering ß- and ¥-cleavage of APP. Neurobiol Aging 2009;30(7):1091-1098.

• Bjerke M, Portelius E, Minthon L, Wallin A, Anckarsater H, et al. Confounding factors influencing amyloid Beta concentration in cerebrospinal fluid. Internat J Alz Dis 2010 pii: 986310.)

• Koike MA, Garcia FG, Kitazawa M, Green KN, Laferla FM. Long term changes in phospho-APP and tau aggregation in the 3xTg-AD mice following cerebral ischemia. Neurosci Lett 2011;495(1):55-9. E-pub 2011 Mar 23.

• Tran HT, LaFerla FM, Holtzman DM, Brody DL. Controlled cortical impact traumatic brain injury in 3xTg-AD mice causes acute intra-axonal amyloid-beta accumulation and independently accelerates the development of tau abnormalities. J Neurosci 2011;31(26):9513–9525.

©2012 American Academy of Neurology

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