Clogging the brain with amyloid-β drives up oxidative stress and stunts cerebral blood flow—and a new study solidifies a critical role for the cell surface receptor CD36 in these shenanigans. Researchers led by Costantino Iadecola at Weill Medical College of Cornell University, New York, report that CD36-deficient AD transgenic mice lack the vascular dysfunction that afflicts control AD mice. The findings were published online March 7 in the Proceedings of the National Academy of Sciences U.S.A.

Berislav Zlokovic of the University of Rochester Medical Center, New York, said the new work offers “definitive evidence” that CD36 is an “absolute requirement” for Aβ-derived oxidative stress in the brain. The findings establish the receptor as “an important new therapeutic target for Aβ-related neurovascular dysfunction,” Zlokovic wrote in an e-mail to ARF (see full comment below).

Broadly speaking, researchers suspect that the health or disease of a person’s brain vasculature is one factor that determines how long a cognitively normal people can withstand the effects of amyloid deposits in their brains. Beyond misshapen blood vessels and reduced blood flow in the brains of AD patients (Iadecola, 2004), a growing literature supports the contribution of vascular damage to this deadly neurodegenerative disorder (see Iadecola, 2010 and Zlokovic, 2008 reviews, and ARF Live Discussion). Epidemiological data reveal that cerebrovascular diseases and AD share similar risk factors (de la Torre, 2010), and brain damage caused by stroke has been shown to intensify the cognitive impairment linked to amyloid plaques and neurofibrillary tangles (Schneider and Bennett, 2010; Snowdon, 2003).

The present study drew inspiration from a 1996 Nature paper with in-vitro data suggesting that Aβ could trigger an outpouring of free radicals that disrupts blood vessel structure and function (Thomas et al., 1996). A junior professor at the University of Minnesota, Minneapolis, at the time, Iadecola wanted to see whether this sort of vascular damage occurred in vivo—that is, in the brains of mice made by colleague Karen Hsiao Ashe—the Tg2576 strain that overproduces mutant human amyloid precursor protein (APP).

Indeed, Tg2576 mice did have problems with their cerebral blood vessels. “The effect was so powerful that you could essentially genotype the mice using vascular assays,” Iadecola told ARF. For those analyses, first author Laibaik Park and colleagues drilled 2 mm-wide holes into the somatosensory cortex of anesthetized mice, then inserted laser probes to measure blood circulation in response to stimuli that enhance blood flow. In one experiment, the researchers applied acetylcholine, a vasodilator, onto the cranial window; in another, they tickled the mouse’s whiskers to spike local neuron activity. Wild-type mice ramped up blood circulation in response to these stimuli. However, the Aβ-overproducing Tg2576 mice had trouble responding in like fashion. Their endothelial vessels did not widen in response to acetylcholine, and the blood flow changes typically induced by neural activity did not occur. “Since then, we’ve been looking at the mechanisms involved,” Iadecola said. “How does Aβ do this?”

His team did several experiments measuring blood flow changes to show that Aβ was, in fact, responsible for the neurovascular impairments. One assay involved bathing the exposed brain surface with fluid containing 5-micromolar Aβ1-40. In another experiment, the researchers infused Aβ directly into cerebral arteries. Using both methods, Aβ exposure made wild-type mice less capable of increasing blood flow in response to whisker tickling or acetylcholine.

Meanwhile, Iadecola’s lab found that Tg2576 mice lacking the catalytic subunit Nox2 of NADPH oxidase did not develop oxidative stress, cerebrovascular abnormalities, or behavioral problems (Park et al., 2008). This suggested that the circulatory deficits seen in AD mice are mediated through the NADPH system. Other studies implicated CD36 as a molecular link by showing that CD36 binds fibrillar Aβ and triggers NADPH-dependent production of free radicals in monocytic cells (Silverstein and Febbraio, 2009; Coraci et al., 2002; Bamberger et al., 2003), and that Aβ-induced pro-inflammatory responses do not occur in microglia isolated from CD36-null mice (El Khoury et al., 2003).

Whereas prior studies suggested CD36 as a key mediator of Aβ's vascular and inflammatory effects, the current paper examines its role in vivo. They used cranial window assays in CD36-knockout mice and in Tg2576 mice crossed onto a CD36-deficient background. Mice normally express CD36 predominantly in cerebral endothelial cells, with stronger immunohistochemical staining in AD mice than in wild-type littermates.

In the whisker stimulation and acetylcholine assays, CD36-knockout mice resisted the cerebrovascular deficits seen in wild-type mice after Aβ was dripped directly on the brain or infused into cerebral arteries. Anti-CD36 antibodies infused into the vessels blocked Aβ-induced impairments in wild-type mice. And Tg2576 mice lacking CD36 were similarly protected from Aβ-induced cerebrovascular dysfunction in the whisker stimulation and acetylcholine assays. These effects did not stem from differences in Aβ production, as both Tg2576 and CD36-/- Tg2576 mice had comparable brain concentrations of Aβ1-40 and Aβ1-42, by ELISA.

In several assays of oxidative stress, CD36-null Tg2576 mice produced far lower levels of free radicals in response to soluble human Aβ1-40 infused into cerebral arteries, compared to AD mice with wild-type CD36.

The Tg2576 mice in these studies were analyzed at three to four months of age, before they develop amyloid plaques or behavioral deficits. “We are now aging the mice for a robust analysis of the effect of CD36 on cognitive function in Tg2576 mice,” Iadecola noted.

Based on the current findings, it appears that “Aβ acts on CD36 in or near blood vessels to produce free radicals, which then paralyze the vessels and make them less able to respond to stimuli that normally allow them to regulate blood flow in the brain,” Iadecola said. “And when the vessels don’t work properly, their ability to clear Aβ is also going to be reduced.” Whether that holds true may be seen when the researchers examine older mice with plaque pathology.—Esther Landhuis.

Reference:
Park L, Wang G, Zhou P, Zhou J, Pitstick R, Previti ML, Younkin L, Younkin SG, Van Nostrand WE, Cho S, Anrather J, Carlson GA, Iadecola C. Scavenger receptor CD36 is essential for the cerebrovascular oxidative stress and neurovascular dysfunction induced by amyloid-{β} Proc Natl Acad Sci U S A. 2011 Mar 7. Abstract

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  1. This is an important study focusing on cerebrovascular dysfunction as a key target of Aβ pathogenic effects. Constantino Ladecola and colleagues have been studying for several years the role of oxidative stress in cerebral vessels, and more specifically, NADPH oxidase-dependent oxidant stress. In the present seminal work, they provide definitive evidence that CD36 scavenger receptor in brain endothelium is an absolute requirement for Aβ oxidant stress via NADPH oxidase. This establishes CD36 as a new important therapeutic target for Aβ-related neurovascular dysfunction.

    View all comments by Berislav Zlokovic

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Other Citations

  1. ARF Live Discussion

Further Reading

Papers

  1. . Scavenger receptor CD36 is essential for the cerebrovascular oxidative stress and neurovascular dysfunction induced by amyloid-beta. Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):5063-8. PubMed.
  2. . The overlap between neurodegenerative and vascular factors in the pathogenesis of dementia. Acta Neuropathol. 2010 Sep;120(3):287-96. PubMed.
  3. . The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron. 2008 Jan 24;57(2):178-201. PubMed.

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  1. Vascular Factors in Alzheimer's Disease

Primary Papers

  1. . Scavenger receptor CD36 is essential for the cerebrovascular oxidative stress and neurovascular dysfunction induced by amyloid-beta. Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):5063-8. PubMed.