Title: Brain expression of the vascular endothelial growth factor gene family in cognitive aging and alzheimer’s disease

Abstract

Vascular endothelial growth factor (VEGF) is associated with the clinical manifestation of Alzheimer’s disease (AD). However, the role of the VEGF gene family in neuroprotection is complex due to the number of biological pathways they regulate. This study explored associations between brain expression of VEGF genes with cognitive performance and AD pathology. Genetic, cognitive, and neuropathology data were acquired from the Religious Orders Study and Rush Memory and Aging Project. Expression of ten VEGF ligand and receptor genes was quantified using RNA sequencing of prefrontal cortex tissue. Global cognitive composite scores were calculated from 17 neuropsychological tests. β-amyloid and tau burden were measured at autopsy. Participants (n = 531) included individuals with normal cognition (n = 180), mild cognitive impairment (n = 148), or AD dementia (n = 203). Mean age at death was 89 years and 37% were male. Higher prefrontal cortex expression of VEGFB, FLT4, FLT1, and PGF was associated with worse cognitive trajectories (p ≤ 0.01). Increased expression of VEGFB and FLT4 was also associated with lower cognition scores at the last visit before death (p ≤ 0.01). VEGFB, FLT4, and FLT1 were upregulated among AD dementia compared with normal cognition participants (p ≤ 0.03). All fourmore » genes associated with cognition related to elevated β-amyloid (p ≤ 0.01) and/or tau burden (p ≤ 0.03). VEGF ligand and receptor genes, specifically genes relevant to FLT4 and FLT1 receptor signaling, are associated with cognition, longitudinal cognitive decline, and AD neuropathology. Future work should confirm these observations at the protein level to better understand how changes in VEGF transcription and translation relate to neurodegenerative disease.« less

Authors:

Mahoney, Emily R. ^[1]; Dumitrescu, Logan ^[1]; Moore, Annah M. ^[1]; Cambronero, Francis E. ^[1]; De Jager, Philip L.  ^[2];

• Search DOE PAGES for author "De Jager, Philip L."
• Search DOE PAGES for ORCID "0000-0002-8057-2505"

Koran, Mary Ellen I. ^[3]; Petyuk, Vladislav A.  ^[4];

• Search DOE PAGES for author "Petyuk, Vladislav A."
• Search DOE PAGES for ORCID "0000-0003-4076-151X"

Robinson, Rena ^[1]; Goyal, Sandeep ^[1]; Schneider, Julie A. ^[5]; Bennett, David A. ^[5]; Jefferson, Angela L. ^[1]; Hohman, Timothy J.  ^[1]

• Search DOE PAGES for author "Hohman, Timothy J."
• Search DOE PAGES for ORCID "0000-0002-3377-7014"

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+ Show Author Affiliations

1. Vanderbilt Univ., Nashville, TN (United States)
2. Columbia University Medical Center, New York, NY (United States); Cell Circuits Program, Broad Institute, Cambridge, MA (United States)
3. Stanford Univ., CA (United States)
4. Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
5. Rush University Medical Center, Chicago, IL (United States)

Publication Date:

Mon Jul 22 00:00:00 EDT 2019

Research Org.:

Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Sponsoring Org.:

USDOE

OSTI Identifier:

1779283

Report Number(s):

PNNL-SA-147565
Journal ID: ISSN 1359-4184

Grant/Contract Number:  

AC05-76RL01830

Resource Type:

Accepted Manuscript

Journal Name:

Molecular Psychiatry

Additional Journal Information:

Journal Volume: 26; Journal Issue: 3; Journal ID: ISSN 1359-4184

Publisher:

Springer

Country of Publication:

United States

Language:

English

Subject:

60 APPLIED LIFE SCIENCES; vascular endothelial; cognitive aging; Alzheimer’s disease