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 four 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.

Blast-Related Mild TBI Alters Anxiety-Like Behavior and Transcriptional Signatures in the Rat Amygdala

“…In comparison to the subtle effects between sham and blast at each time-point, when we compared the transcriptome of sham animals at the chronic vs. sub-acute time-points, we found an abundance of genes differentially expressed and surviving correction for multiple testing. These changes emphasize the large effect of aging on gene expression in the amygdala, and we identified significant alterations in expression levels of various genes that have previously been associated with normal aging and neurodegeneration, including Gfap (Rodríguez et al, 2014), Vegfb (Mahoney et al, 2019), FIGURE 6 | Gene ontology enrichment using Ingenuity Pathway Analysis (IPA). (A) Top 10 gene categories.…”

“…Significant interactions included Plpp3, which is enriched in the ventral midbrain and has been linked to dopaminergic functioning in the striatum but not yet linked to the amygdala function (Gómez-López et al, 2016). Of the abundant interactions that did not survive multiple testing correction, we chose to highlight four additional genes that have known roles in brain injury and/or amygdala functioning, including Apoe (Klein et al, 2014;Tang et al, 2015), Reln (Boyle et al, 2011;Frankowski et al, 2019), Vegfb (Wu et al, 2008;Savalli et al, 2014;Mahoney et al, 2019), and Bdnf (Wu et al, 2008;Guilloux et al, 2012;Sagarkar et al, 2017), which are all crucial mediators of synaptic plasticity and neurotransmission as well as structure and function of brain vasculature. Interestingly, Plpp3, Apoe, Reln, and Vegfb show similar patterns of interaction, such that expression levels in blast animals are higher than sham animals at the sub-acute timepoint but lower than sham animals at the chronic time point.…”

Sex-Dependent Shared and Non-Shared Genetic Architecture Across Mood and Psychotic Disorders

“…Genes involved in regulation of VEGF signaling were enriched among GxS loci for MDD in our analyses. Sex differences have been observed in serum VEGF levels throughout life (91), and brain expression of VEGF has been associated with cognitive aging and Alzheimer's disease (92,93). Further, the strongest GxS interaction was detected for SCZ in the 5' UTR of MOCOS (rs11665282; p=1.48×10 −7 ), which, based on evaluation of brain expression datasets, is highly expressed in endothelial cells lining blood vessels (Supplementary Figure 24).…”

Asymmetric dimethylarginine exacerbates cognitive dysfunction associated with cerebrovascular pathology

“…Metabolic syndrome (a primary risk factor of VCID) is frequently associated with elevated blood levels of ADMA 7,8 and VEGF 46,47 and increased microvascular pathology in the brain 48 . More recently, studies also reported that patients with cognitive aging and AD had a greater expression of endothelial growth factor gene family, including VEGF, in the brain and serum and the degree of VEGF expression well correlated with the severity of dementia 49,50 . It is of interest note that Tg‐SwDI mice had increased blood levels of VEGF (Figure 7B‐iii) and daily ADMA treatment increased the brain N‐Tyr levels further in Tg‐SwDI mice (Figure 7A).…”