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Apoε4 disrupts neurovascular regulation and undermines white matter integrity and cognitive function.

TitleApoε4 disrupts neurovascular regulation and undermines white matter integrity and cognitive function.
Publication TypeJournal Article
Year of Publication2018
AuthorsKoizumi K, Hattori Y, Ahn SJi, Buendia I, Ciacciarelli A, Uekawa K, Wang G, Hiller A, Zhao L, Voss HU, Paul SM, Schaffer C, Park L, Iadecola C
JournalNat Commun
Volume9
Issue1
Pagination3816
Date Published2018 Sep 19
ISSN2041-1723
Abstract

The ApoE4 allele is associated with increased risk of small vessel disease, which is a cause of vascular cognitive impairment. Here, we report that mice with targeted replacement (TR) of the ApoE gene with human ApoE4 have reduced neocortical cerebral blood flow compared to ApoE3-TR mice, an effect due to reduced vascular density rather than slowing of microvascular red blood cell flow. Furthermore, homeostatic mechanisms matching local delivery of blood flow to brain activity are impaired in ApoE4-TR mice. In a model of cerebral hypoperfusion, these cerebrovascular alterations exacerbate damage to the white matter of the corpus callosum and worsen cognitive dysfunction. Using 3-photon microscopy we found that the increased white matter damage is linked to an enhanced reduction of microvascular flow resulting in local hypoxia. Such alterations may be responsible for the increased susceptibility to hypoxic-ischemic lesions in the subcortical white matter of individuals carrying the ApoE4 allele.

DOI10.1038/s41467-018-06301-2
Alternate JournalNat Commun
PubMed ID30232327
PubMed Central IDPMC6145902
Grant ListR01 NS097805 / NS / NINDS NIH HHS / United States
R01 NS100447 / NS / NINDS NIH HHS / United States
097805 / / U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) /
100447 / / U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) /