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Scavenger receptor CD36 is essential for the cerebrovascular oxidative stress and neurovascular dysfunction induced
Laibaik Park1, Gang Wang, Ping Zhou
1Division of Neurobiology, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10065, USA.
Insights
The scavenger receptor CD36 links amyloid-β (Aβ) to vascular oxidative stress, a key factor in Alzheimer's dementia (AD) neurovascular dysfunction. Targeting CD36 may offer a therapeutic strategy for AD-related cerebrovascular issues.
Area of Science:
- Neuroscience
- Vascular Biology
- Biochemistry
Background:
- Cerebrovascular dysfunction is increasingly implicated in Alzheimer's dementia (AD) pathogenesis.
- Amyloid-β (Aβ) peptides exert vascular effects, largely via NADPH oxidase-generated reactive oxygen species.
- The precise mechanisms connecting Aβ to vascular oxidative stress remain unclear.
Purpose of the Study:
- To elucidate the mechanisms linking Aβ to NADPH oxidase-dependent vascular oxidative stress.
- To investigate the role of the scavenger receptor CD36 in Aβ-induced neurovascular dysfunction.
- To determine if CD36 is a potential therapeutic target for AD-related cerebrovascular dysfunction.
Main Methods:
- Topical application of Aβ1-40 onto the somatosensory cortex of wild-type (WT) and CD36-null (CD36(0/0)) mice.
- Intracerebral arterial infusion of Aβ1-40 in WT mice with and without CD36 blocking antibodies.
- Assessment of neurovascular dysfunction in CD36(0/0) mice and Tg2576 transgenic AD model mice.
- Measurement of vascular oxidative stress in response to Aβ1-40.
Main Results:
- CD36 is essential for Aβ1-40-induced vascular oxidative stress and neurovascular dysfunction.
- Aβ1-40 failed to attenuate cerebral blood flow increases in CD36-null mice.
- CD36 deficiency prevented Aβ-induced neurovascular dysfunction in Tg2576 mice, despite elevated Aβ levels.
- CD36 mediates vascular oxidative stress induced by exogenous Aβ1-40 and observed in AD models.
Conclusions:
- CD36 acts as a critical mediator linking Aβ1-40 to NADPH oxidase-dependent vascular oxidative stress.
- This oxidative stress contributes significantly to the neurovascular dysfunction observed in Alzheimer's dementia.
- CD36 represents a promising therapeutic target for mitigating cerebrovascular dysfunction in AD.
Abstract:
Increasing evidence indicates that cerebrovascular dysfunction plays a pathogenic role in Alzheimer's dementia (AD). Amyloid-β (Aβ), a peptide central to the pathogenesis of AD, has profound vascular effects mediated, for the most part, by reactive oxygen species produced by the enzyme NADPH oxidase. The mechanisms linking Aβ to NADPH oxidase-dependent vascular oxidative stress have not been identified, however. We report that the scavenger receptor CD36, a membrane glycoprotein that binds Aβ, is essential for the vascular oxidative stress and neurovascular dysfunction induced by Aβ1-40. Thus, topical application of Aβ1-40 onto the somatosensory cortex attenuates the increase in cerebral blood flow elicited by neural activity or by endothelium-dependent vasodilators in WT mice but not in CD36-null mice (CD36(0/0)). The cerebrovascular effects of infusion of Aβ1-40 into cerebral arteries are not observed in mice pretreated with CD36 blocking antibodies or in CD36(0/0) mice. Furthermore, CD36 deficiency prevents the neurovascular dysfunction observed in transgenic mice overexpressing the Swedish mutation of the amyloid precursor protein Tg2576 despite elevated levels of brain Aβ1-40. CD36 is also required for the vascular oxidative stress induced by exogenous Aβ1-40 or observed in Tg2576 mice. These observations establish CD36 as a key link between Aβ1-40 and the NADPH oxidase-dependent vascular oxidative stress underlying the neurovascular dysfunction and suggest that CD36 is a potential therapeutical target to counteract the cerebrovascular dysfunction associated with Aβ.
