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P4‐065: APOE4 CONDITIONALLY EXPRESSED IN CEREBROVASCULATURE IMPAIRS ENDOTHELIAL FUNCTIONS AND INDUCES COGNITIVE DEFICITS
Author(s) -
Yamazaki Yu,
Liu Chia-Chen,
Oue Hiroshi,
Kurti Aishe,
Yamazaki Akari,
Fryer John D.,
Kanekiyo Takahisa,
Bu Guojun
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.06.2468
Subject(s) - apolipoprotein e , biology , phenotype , allele , population , mural cell , cell type , microbiology and biotechnology , endocrinology , medicine , neuroscience , immunology , cell , vascular smooth muscle , gene , disease , genetics , environmental health , smooth muscle
Specifically, patients with AD exhibit deficits in neurovascular coupling (NVC, increased cerebral blood flow evoked by neuronal activation), which is recapitulated in various mouse models of AD. We have previously identified the mammalian/mechanistic target of rapamycin (mTOR) as a major driver of brain vascular dysfunction in AD. Therefore, the aims of the present study were to 1) establish themTOR-dependent contribution to NVC deficits in ADmice, and 2) define the mechanisms of mTOR-mediated neuronal nitric oxide synthase (nNOS) insensitivity using in vivo and in vitro techniques. Methods: Male J20 micewere fed chow containing encapsulated rapamycin or vehicle for either 8 months (older group only) or 8 weeks (both ages). Fear conditioning was performed at either 6 or 12 months of age, followed by laser Doppler flowmetery to measure neurovascular coupling in response to whisker stimulation. In vitro studies were performed in cultured N2A or B103 neuroblastoma cell lines. Results: J20 mice at 6 and 12 months old had profound impairments in NVC, particularly in the nNOS-mediated component of NVC, which was preserved by attenuation of mTOR activity with rapamycin treatment for 8 weeks. Further, NVC deficits were present prior to cognitive impairments, as contextual memory was not significantly impaired in the 6MO mice. Our in vitro studies indicate that mTOR inhibition with rapamycin increases nNOS activation as measured by the phosphorylation of Ser1177. Conclusions: These studies establish that mTOR drives the loss of the nNOS component of NVC in an AD mouse model, possibly by inhibiting nNOS phosphorylation at Ser1177. Funding: CVS: AARF-17-504221 and NIA-T32AG021890. ABO: NIA-T32AG021890. SFH: R25NS080684. VG: 1-I01BX002211-01A2 VA Merit Award, Owens Foundation, SAMF, NIA/NIH-P30-AG013319-21 Nathan Shock Center of Excellence, and RL Bailey and daughter LK Bailey Alzheimer’s Fund. 1. Iturria-Medina et al. Early role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis. Nature communications. 2016. 2.Van Skike CE and Galvan V. A Perfect sTORm: The Role of the Mammalian Target of Rapamycin (mTOR) in Cerebrovascular Dysfunction of Alzheimer’s Disease. Gerontology. 2018.