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Genetic Expression Profile of Cerebrovascular Endothelium During Development of Alzheimer's Disease
Author(s) -
Nye Phoebe P.,
Behringer Erik J.
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.518.1
Subject(s) - purinergic receptor , endothelium , cognitive decline , intracellular , vasodilation , hyperpolarization (physics) , receptor , medicine , gene isoform , endocrinology , neuroscience , biology , chemistry , microbiology and biotechnology , gene , dementia , biochemistry , disease , organic chemistry , nuclear magnetic resonance spectroscopy
In 2018 alone, seven‐hundred thousand Americans of age 65 years and older will have a form of Alzheimer's disease (AD) by the end of their lives. Emerging evidence demonstrates the association of AD with impaired delivery of blood oxygen and nutrients to and throughout the brain. Cerebral arteries coordinate vasodilation through endothelium‐derived hyperpolarization (EDH); sequentially entailing stimulation of G protein‐coupled receptors (GPCRs), increases in intracellular Ca 2+ , activation of small‐ and intermediate‐conductance Ca 2+ ‐activated K + channels (SK Ca /IK Ca ), and spread of negative intracellular charge (“hyperpolarization”) through cell‐to‐cell gap junctions. Thus, we tested the hypothesis that the genetic expression of EDH vasodilatory components may decline during progression of age‐related AD in mouse cerebrovascular endothelium . We used the triple mutation mouse model of AD (3xTgAD) to examine cerebrovascular genetic profiles for young control (YC; 1 to 2 mo), mild cognitive impairment (MCI; 4 to 5 mo), amyloid‐β plaques (Aβ; 6 to 8 mo), and plaques + neurofibrillary tangles (Aβ+Tau; ≥12 mo); 3 male and 3 female mice/group. Quantitative polymerase chain reaction (qPCR) and RNA sequencing were used to examine genetic expression of isolated cerebral artery endothelium and purified brain vessels respectively. The qPCR results demonstrate mixed expression of respective isoforms of purinergic receptors as indicated by no changes for P2ry1 (transcript for P2Y1) but ~35% and ~65% upregulation of P2ry2 (P2Y2) during Aβ and Aβ+Tau respectively. In contrast, the expression of ion channel mRNA in the form of major K + channels ( Kcnn3 / Kcnn4 , SK Ca /IK Ca & Kcnj2 , inward rectifying K IR 2.1) and transient receptor potential channels ( Trpv4 , TRPV4) remains relatively stable throughout the life of the animal. Further, with the exception of Gja1 (Cx43), the expression of connexins composing gap junctions ( Gja4 , Cx37 & Gja5 , Cx40) increased by ≥ 20% during Aβ and Aβ+Tau. Finally, RNAseq data and pathway analysis demonstrate a >two‐fold upregulation of genes integral to cardiovascular remodeling during Aβ+Tau vs. YC. Overall, these data indicate profound genetic alterations underlying cerebral blood vessel function corresponding to moment‐to‐moment regulation of blood flow and chronic maintenance of vascular structure. Pairing new found knowledge of vascular “signatures” with developmental phases of AD may offer unprecedented opportunities to maintain a healthy mind throughout the entirety of a standard lifespan (~80 to 100 years). Support or Funding Information This research is supported by Loma Linda University School of Medicine new faculty start‐up funds and National Institutes of Health grants R00AG047198 & R56AG062169 (EJB). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .