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

Kenzo Koizumi, Yorito Hattori, Sung Ji Ahn, Izaskun Buendia, Antonio Ciacciarelli, Ken Uekawa, Gang Wang, Abigail Hiller, Lingzhi Zhao, Henning U. Voss, Steven M. Paul, Chris Schaffer, Laibaik Park, Costantino Iadecola

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

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.

Original languageEnglish
Article number3816
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

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