VEGF Paradoxically Reduces Cerebral Blood Flow in Alzheimer’s Disease Mice

Ali, Muhammad; Bracko, Oliver

doi:10.1177/26331055221109254

Cited by 17 publications

(9 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, it has been demonstrated that AD patients also express higher levels of VEGF within certain cerebral tissue regions (Ali et al., 2022 ; Mahoney et al., 2021 ; Thomas et al., 2015 ), while cerebral capillary specific expression of VEGF is depleted within AD patients (Provias & Jeynes, 2014 ), which coincides with our in vitro and in vivo results. Additionally, cerebral VEGF overexpression within the AD brain has been linked to pericyte loss, capillary stalls, increases in BBB permeability, decreased CBF and increased AD pathology (Ali & Bracko, 2022 ; Mahoney et al., 2021 ), indicating a maladaptive overexpression. It is becoming more accepted that aberrant VEGF/VEGFR2 signaling plays a large role within promoting AD pathology and cognitive decline and this study has begun to demonstrate that this maladaptive VEGF/VEGFR2 signaling, typical in dementia, may be exacerbated within Tg2576 mice with Hhcy.…”

Section: Discussionmentioning

confidence: 99%

Homocysteine potentiates amyloid β‐induced death receptor 4‐ and 5‐mediated cerebral endothelial cell apoptosis, blood brain barrier dysfunction and angiogenic impairment

Carey,

Parodi‐Rullan,

Vazquez‐Torres

et al. 2024

Aging Cell

View full text Add to dashboard Cite

Cerebrovascular dysfunction has been implicated as a major contributor to Alzheimer's Disease (AD) pathology, with cerebral endothelial cell (cEC) stress promoting ischemia, cerebral‐blood flow impairments and blood–brain barrier (BBB) permeability. Recent evidence suggests that cardiovascular (CV)/cerebrovascular risk factors, including hyperhomocysteinemia (Hhcy), exacerbate AD pathology and risk. Yet, the underlying molecular mechanisms for this interaction remain unclear. Our lab has demonstrated that amyloid beta 40 (Aβ40) species, and particularly Aβ40‐E22Q (AβQ22; vasculotropic Dutch mutant), promote death receptor 4 and 5 (DR4/DR5)‐mediated apoptosis in human cECs, barrier permeability, and angiogenic impairment. Previous studies show that Hhcy also induces EC dysfunction, but it remains unknown whether Aβ and homocysteine function through common molecular mechanisms. We tested the hypotheses that Hhcy exacerbates Aβ‐induced cEC DR4/5‐mediated apoptosis, barrier dysfunction, and angiogenesis defects. This study was the first to demonstrate that Hhcy specifically potentiates AβQ22‐mediated activation of the DR4/5‐mediated extrinsic apoptotic pathway in cECs, including DR4/5 expression, caspase 8/9/3 activation, cytochrome‐c release and DNA fragmentation. Additionally, we revealed that Hhcy intensifies the deregulation of the same cEC junction proteins mediated by Aβ, precipitating BBB permeability. Furthermore, Hhcy and AβQ22, impairing VEGF‐A/VEGFR2 signaling and VEGFR2 endosomal trafficking, additively decrease cEC angiogenic capabilities. Overall, these results show that the presence of the CV risk factor Hhcy exacerbates Aβ‐induced cEC apoptosis, barrier dysfunction, and angiogenic impairment. This study reveals specific mechanisms through which amyloidosis and Hhcy jointly operate to produce brain EC dysfunction and death, highlighting new potential molecular targets against vascular pathology in comorbid AD/CAA and Hhcy conditions.

show abstract

Section: Discussionmentioning

confidence: 99%

Homocysteine potentiates amyloid β‐induced death receptor 4‐ and 5‐mediated cerebral endothelial cell apoptosis, blood brain barrier dysfunction and angiogenic impairment

Carey,

Parodi‐Rullan,

Vazquez‐Torres

et al. 2024

Aging Cell

View full text Add to dashboard Cite

show abstract

“…[ 35 ] Furthermore, VEGF-A signaling contributes to leukocyte stalling in brain capillaries and reduces cerebral blood flow in a mouse model of AD. [ 36 ] Conversely, upregulation of VEGF expression has been shown to enhance neurotransmission, synaptic plasticity mechanisms, and neurogenesis. [ 37 ] Multiple studies have suggested that inhibition of EGFR can improve astrogliosis, augment autophagy, alleviate Aβ toxicity and neuroinflammation, and promote axonal regeneration following injury.…”

Section: Discussionmentioning

confidence: 99%

Exploring Acori Tatarinowii Rhizoma and Polygalae Radix in Alzheimer’s: Network pharmacology and molecular docking analysis

Tong,

Cheng,

Tie

et al. 2024

Medicine

View full text Add to dashboard Cite

Explore Acori Tatarinowii Rhizoma (ATR) and Polygalae Radix (PR) mechanisms in Alzheimer’s disease (AD) treatment through network pharmacology. ATR-PR was investigated in the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, Batman, and Traditional Chinese Medicines Integrated Database (TCMID) to gather information on its chemical components and target proteins. Target genes associated with AD were retrieved from the GeneCards and National Center for Biotechnology Information (NCBI) databases. The integration of these datasets with potential targets facilitated the construction of an AD and ATR-PR protein-protein interaction (PPI) network using the STRING database. The resulting network identified the core active ingredients and main targets of ATR-PR in AD treatment. Cluster analysis of the PPI network was performed using Cytoscape 3.7.1. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted using the Metascape database. Molecular docking simulations revealed potential interactions between the main active ingredients and core targets. Our analysis identified 8 putative components and 455 targets of ATR-PR. We systematically searched for 1306 genes associated with AD, conducted Venn diagram analysis resulting in 156 common targets, and constructed a PPI network with 57 key targets. GO functional analysis highlighted the primary biological processes associated with oxidative stress. KEGG pathway enrichment analysis revealed the involvement of 64 signaling pathways, with the PI3K/Akt signaling pathway playing a key role. Molecular docking analysis indicated a high affinity between the potential targets of ATR-PR and the main compounds of AD. This study sheds light on the complex network of interactions involving ATR-PR in the context of AD. The identified targets, pathways, and interactions provide a foundation for understanding the potential therapeutic mechanisms. The involvement of oxidative stress-related processes and the crucial role of the PI3K/Akt signaling pathway suggest avenues for targeted therapeutic interventions in Alzheimer’s disease treatment. Our proposition of the combined use of ATR-PR has emerged as a potential treatment strategy for AD, supported by a network pharmacology approach. This framework provides a robust foundation for future clinical applications and experimental research in the pursuit of effective Alzheimer’s disease treatments.

show abstract

“…Frontiers in Pharmacology frontiersin.org angiogenic functions, leading to cerebral capillary stasis and reductions in blood flow as a presumed mechanism of accelerated cognitive decline (Ali and Bracko, 2022). These pieces of evidence point to the hypothesis that age-related changes in the vascular system are linked to chronic neuroinflammation, progressive deleterious impact on cognitive functions and neuronal death.…”

Section: Neuroinflammation and Immunosenescence In Alzheimer´s Diseasementioning

confidence: 96%

Revisiting the neuroinflammation hypothesis in Alzheimer’s disease: a focus on the druggability of current targets

et al. 2023

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is the most common form of neurodegenerative disease and disability in the elderly; it is estimated to account for 60%–70% of all cases of dementia worldwide. The most relevant mechanistic hypothesis to explain AD symptoms is neurotoxicity induced by aggregated amyloid-β peptide (Aβ) and misfolded tau protein. These molecular entities are seemingly insufficient to explain AD as a multifactorial disease characterized by synaptic dysfunction, cognitive decline, psychotic symptoms, chronic inflammatory environment within the central nervous system (CNS), activated microglial cells, and dysfunctional gut microbiota. The discovery that AD is a neuroinflammatory disease linked to innate immunity phenomena started in the early nineties by several authors, including the ICC´s group that described, in 2004, the role IL-6 in AD-type phosphorylation of tau protein in deregulating the cdk5/p35 pathway. The “Theory of Neuroimmunomodulation”, published in 2008, proposed the onset and progression of degenerative diseases as a multi-component “damage signals” phenomena, suggesting the feasibility of “multitarget” therapies in AD. This theory explains in detail the cascade of molecular events stemming from microglial disorder through the overactivation of the Cdk5/p35 pathway. All these knowledge have led to the rational search for inflammatory druggable targets against AD. The accumulated evidence on increased levels of inflammatory markers in the cerebrospinal fluid (CSF) of AD patients, along with reports describing CNS alterations caused by senescent immune cells in neuro-degenerative diseases, set out a conceptual framework in which the neuroinflammation hypothesis is being challenged from different angles towards developing new therapies against AD. The current evidence points to controversial findings in the search for therapeutic candidates to treat neuroinflammation in AD. In this article, we discuss a neuroimmune-modulatory perspective for pharmacological exploration of molecular targets against AD, as well as potential deleterious effects of modifying neuroinflammation in the brain parenchyma. We specifically focus on the role of B and T cells, immuno-senescence, the brain lymphatic system (BLS), gut-brain axis alterations, and dysfunctional interactions between neurons, microglia and astrocytes. We also outline a rational framework for identifying “druggable” targets for multi-mechanistic small molecules with therapeutic potential against AD.

show abstract

VEGF Paradoxically Reduces Cerebral Blood Flow in Alzheimer’s Disease Mice

Cited by 17 publications

References 34 publications

Homocysteine potentiates amyloid β‐induced death receptor 4‐ and 5‐mediated cerebral endothelial cell apoptosis, blood brain barrier dysfunction and angiogenic impairment

Homocysteine potentiates amyloid β‐induced death receptor 4‐ and 5‐mediated cerebral endothelial cell apoptosis, blood brain barrier dysfunction and angiogenic impairment

Exploring Acori Tatarinowii Rhizoma and Polygalae Radix in Alzheimer’s: Network pharmacology and molecular docking analysis

Revisiting the neuroinflammation hypothesis in Alzheimer’s disease: a focus on the druggability of current targets

Contact Info

Product

Resources

About